Submissions for variant NM_145239.3(PRRT2):c.649dup (p.Arg217fs)

Total submissions: 66

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000188779	SCV000203360	pathogenic	not provided	2014-04-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000188779	SCV000242403	pathogenic	not provided	2020-03-23	criteria provided, single submitter	clinical testing	Published functional studies indicate this variant results in decreased expression and altered cellular localization of the protein (Wu et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene; This variant is associated with the following publications: (PMID: 25522171, 23180180, 25502464, 23535490, 22877996, 22782515, 24661410, 22744660, 24370076, 27959697, 30182498, 30034362, 29250726, 31785815, 31901402, 31302675, 29655203, 26876767, 22101681, 25595153, 22243967, 23768507, 24074546, 22845787, 23771590, 23182655, 23126439, 24609974, 23532549, 22870186, 22623405, 27920401, 25915028, 27123484, 27172900, 28553402, 28097321, 28566192, 28525812, 29215089, 29778030, 29852413, 28018471, 29285950, 29302074, 30501978, 29132464, 30392205, 30125676, 30847922, 30814447, 31780880, 31737037, 31154286, 31722684, 32002278, 31216405, 32246320, 33126500, 34489640, 34298454, 32651081, 33391346, 33327426, 32613771, 33043084, 33258288, 32964447, 25667652, 25457817, 32860008, 33726816, 32237035)
Genetic Services Laboratory, University of Chicago	RCV000193894	SCV000248604	pathogenic	Seizure	2014-06-05	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000188779	SCV000281646	pathogenic	not provided	2014-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV000791409	SCV000291481	pathogenic	Episodic kinesigenic dyskinesia	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg217Profs*8) in the PRRT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic (PMID: 22623405, 22744660). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with infantile seizures and/or paroxysmal kinesigenic dyskinesia (PKD) (PMID: 22101681, 22870186, 22877996, 23299620, 25667652). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65758). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000188779	SCV000614795	pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population appears higher than would generally be expected for pathogenic variants in this gene, however, the data have failed quality metrics and thus are not useful in evaluating the pathogenicity of this variant (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has not been reported in control populations composed of more than 4,000 samples and varying ethnicities, which is consistent with the pathogenicity of this variant (PMID: 22243967, 22870186, 22875091, 23077024, 23077026, 22399141, 22209761, 22101681, 22131361, 25522171). This variant associates with various PRRT2-related disorders in multiple families, and is also reported to have reduced penetrance and variable expression between and within families (PMID: 23077026, 22782515, 23126439, 22120146, 22623405, 23077017, 23182655, 23771590, 24370076, 25502464). This variant appears to occur de novo in multiple individuals with various PRRT2-related disorders (PMID: 23077026, 22399141).
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000585818	SCV000693768	likely pathogenic	Seizures, benign familial infantile, 2	2018-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313738	SCV000849074	pathogenic	Inborn genetic diseases	2018-04-20	criteria provided, single submitter	clinical testing	The c.649dupC pathogenic mutation, located in coding exon 1 of the PRRT2 gene, results from a duplication of C at nucleotide position 649, causing a translational frameshift with a predicted alternate stop codon (p.R217Pfs*8). This alteration has been detected in many families in the literature with paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD or PKC), familial infantile convulsions and paroxysmal choreoathetosis (ICCA), and benign familial infantile seizures or epilepsy (BFIS or BFIE) (Chen WJ et al. Nat Genet. 2011; 43(12):1252-5; Heron SE et al. Am J Hum Genet. 2012; 90(1):152-60; Lee HY et al. Cell Rep. 2012; 1(1):2-12; Ono S et al. J Hum Genet. 2012; 57(5):338-41; Wang Y et al. Sci Rep, 2017 Jan;7:40319). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768059	SCV000898913	pathogenic	Seizures, benign familial infantile, 2; Episodic kinesigenic dyskinesia 1; Infantile convulsions and choreoathetosis	2018-07-23	criteria provided, single submitter	clinical testing	PRRT2 NM_145239.2 exon 2 p.Arg217Profs*8 (c.649dupC): This variant has been well reported in the literature (including an entry in GeneReviews) and has been identified in several individuals with a variety of presentations, most commonly, benign familial infantile epilepsy, infantile convulsions/choreoathetosis, and paroxysmal kinesigenic dyskinesia, segregating with disease in several affected family members (Chen 2011 PMID:22101681, Dale 2012 PMID:22845787, Heron 2012 PMID:22243967, Castiglioni 2013 PMID:23182655, He 2014 PMID:25522171, Ebrahimi-Fakhari 2015 PMID:26598493, Ebrahimi-Fakhari 2018 PMID:29334453). In addition, a review article suggests that this variant may account for 78.5% of the reported cases in the literature (Ebrahimi-Fakhari 2015 PMID:26598493). This variant is present in 8/29718 alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772994486). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:65758). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an addition of 1 nucleotide within a string of cytosines at position 649 and creates a premature stop codon 8 amino acids downstream from this location, which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Ebrahimi-Fakhari 2015 PMID:26598493). In summary, this variant is classified as pathogenic .
Mendelics	RCV000055991	SCV001140084	pathogenic	Episodic kinesigenic dyskinesia 1	2019-05-28	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000991298	SCV001142699	pathogenic	Paroxysmal nonkinesigenic dyskinesia 1	2019-06-17	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000055991	SCV001149892	pathogenic	Episodic kinesigenic dyskinesia 1	2022-03-07	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000585818	SCV001164113	pathogenic	Seizures, benign familial infantile, 2		criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000055991	SCV001164215	pathogenic	Episodic kinesigenic dyskinesia 1	2018-03-02	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000153783	SCV001167610	pathogenic	Infantile convulsions and choreoathetosis	2018-09-06	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000153783	SCV001192520	pathogenic	Infantile convulsions and choreoathetosis	2019-11-13	criteria provided, single submitter	research	ACMG codes: PVS1, PM1, PP1, PP5
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000153783	SCV001244945	pathogenic	Infantile convulsions and choreoathetosis		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000188779	SCV001248447	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PRRT2: PVS1, PP1:Strong, PS2, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center	RCV000055991	SCV001251443	pathogenic	Episodic kinesigenic dyskinesia 1	2019-10-23	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000153783	SCV001368515	pathogenic	Infantile convulsions and choreoathetosis	2020-03-23	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4,PM1,PP5.
Centogene AG - the Rare Disease Company	RCV000585818	SCV001426446	pathogenic	Seizures, benign familial infantile, 2		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000585818	SCV001428611	pathogenic	Seizures, benign familial infantile, 2	2023-08-07	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4
Institute of Human Genetics, University of Leipzig Medical Center	RCV001264813	SCV001443008	pathogenic	PRRT2 insufficiency	2020-03-01	criteria provided, single submitter	clinical testing	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2, PM3; observed in two families
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000585818	SCV001554493	likely pathogenic	Seizures, benign familial infantile, 2		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000188779	SCV001715149	pathogenic	not provided	2021-05-10	criteria provided, single submitter	clinical testing	PVS1, PS3, PS4, PP1, PP5
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000193894	SCV001737060	likely pathogenic	Seizure		criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000055991	SCV001737112	pathogenic	Episodic kinesigenic dyskinesia 1		criteria provided, single submitter	clinical testing
New York Genome Center	RCV000585818	SCV001760953	pathogenic	Seizures, benign familial infantile, 2	2020-06-05	criteria provided, single submitter	clinical testing	The inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is the duplication of a single nucleotide, resulting in the frameshift and premature termination of the protein approximately 8 amino acids downstream (coding exon 2/4). This variant is found in 21 heterozygous individuals in gnomAD(v3.0), with an allele frequency of 1.49e-4. This variant is reported in ClinVar as Pathogenic (VarID:65758), and is the most common pathogenic PRRT2 variant identified in affected individuals [PMID:29334453; PMID:26598493; PMID:24370076]. Functional studies suggest this variant is subject to rapid nonsense mediated decay [PMID:25457817]. Given this, the inherited c.649dup (p.Arg217ProfsTer8) variant identified in the PRRT2 gene is reported as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001563615	SCV001786591	pathogenic	PRRT2-Associated Paroxysmal Movement Disorders	2021-03-26	criteria provided, single submitter	clinical testing	The PRRT2 c.649dupC (p.Arg217ProfsTer8) variant results in a frameshift and is predicted to result in premature termination or absence of the protein. Across a selection of the available literature, the p.Arg217ProfsTer8 variant has been identified in approximately 78% of all 1444 individuals with published PRRT2 variants (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Lee et al. 2012; Becker et al. 2013; Ebrahimi-Fakhari et al. 2015). The phenotype of affected individuals includes paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions and choreoathetosis. The p.Arg217ProfsTer8 variant was found to segregate with disease in many familial cases with high penetrance, although incomplete penetrance in several families has been described (Chen et al. 2011; Heron et al. 2012; Ono et al. 2012; Becker et al. 2013). The p.Arg217ProfsTer8 variant is reported at a frequency of 0.0001727 in the African/African-American population of the Genome Aggregation Database. PRRT2 is a transmembrane protein, and the p.Arg217ProfsTer8 variant is expected to disrupt the transmembrane domain (Chen et al. 2011). Functional studies demonstrated absence of this truncated protein in transfected cell lines and cultured hippocampal neurons (Lee et al. 2012). Co-transfection of p.Arg217ProfsTer8 with wild-type PRRT2 demonstrated normal expression of wild-type PRRT2 and low/undetectable expression of truncated PRRT2, suggesting haploinsufficiency as the disease mechanism (Lee et al. 2012). Based on the collective evidence and application of ACMG criteria, the variant is classified as pathogenic for PRRT2-associated paroxysmal movement disorders.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000188779	SCV001905656	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
3billion	RCV000585818	SCV002012092	pathogenic	Seizures, benign familial infantile, 2	2021-10-02	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of [0.003103. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000065758.42, PS4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000188779	SCV002019531	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000153783	SCV002059398	pathogenic	Infantile convulsions and choreoathetosis	2021-08-11	criteria provided, single submitter	clinical testing
DASA	RCV000055991	SCV002061239	pathogenic	Episodic kinesigenic dyskinesia 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.649dup;p.(Arg217Profs*8) is a null frameshift variant (NMD) in the PRRT2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65758; PMID: 22101681; 22870186; 22877996; 25667652) - PS4 and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273952	SCV002559023	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002280097	SCV002568212	pathogenic	PRRT2-related disorder	2022-06-15	criteria provided, single submitter	clinical testing	PVS1, PS4, PP1
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000153783	SCV002577560	pathogenic	Infantile convulsions and choreoathetosis	2022-01-21	criteria provided, single submitter	clinical testing	PVS1, PS3, PP5
Institute of Human Genetics, University Hospital Muenster	RCV000193894	SCV002578007	pathogenic	Seizure	2022-08-24	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PS4,PP3,PP5,BS1
MGZ Medical Genetics Center	RCV000055991	SCV002581620	pathogenic	Episodic kinesigenic dyskinesia 1	2022-07-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470742	SCV002767234	pathogenic	Self-limited familial infantile epilepsy	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial infantile convulsions with paroxysmal choreoathetosis (MIM#602066), episodic kinesigenic dyskinesia 1 (MIM#128200), benign familial infantile seizures 2 (MIM#605751) and self-limited familial and non-familial infantile seizures (MONDO#0100024). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Reduced penetrance has been reported for paroxysmal kinesigenic dyskinesia (PMID: 29334453). (I) 0115 - Variants in this gene are known to have variable expressivity. Variation in phenotype has been reported within and between families with the same pathogenic variant (PMID: 29334453). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 718 heterozygotes, 0 homozygotes; variant did not pass quality filter). (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (514 heterozygotes, 0 homozygotes; variant did not pass quality filter). (I) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals (ClinVar, PMIDs: 22101681, 26561923, 25502464). (SP) 0901 - This variant has strong evidence for segregation with disease (PMIDs: 22101681, 25502464). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000768059	SCV002792003	pathogenic	Seizures, benign familial infantile, 2; Episodic kinesigenic dyskinesia 1; Infantile convulsions and choreoathetosis	2022-01-18	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000188779	SCV002818270	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000585818	SCV002820154	pathogenic	Seizures, benign familial infantile, 2		criteria provided, single submitter	clinical testing	The variant c.649dup (p.Arg217ProfsTer8) in gene PRRT2 has been reported in literature in many sporadic and familial cases of paroxysmal kinesigenic dyskinesia (PKD) and/or infantile seizures (Chen et al. 2011, Lee et al. 2012). In the familial cases, co-segregation with disease has been reported. A review article suggests that this variant may account for 78.5% of the reported cases in the literature (Ebrahimi-Fakhari et al. 2015). This sequence change inserts 1 nucleotide in exon 2 of the PRRT2 mRNA (c.649dupC), causing a frameshift at codon 217. This creates a premature translational stop signal (p.Arg217Profs*8) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic. Null variant (frame-shift), in gene PRRT2 for which loss-of-function is a known mechanism of disease. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Likely Pathogenic. The p.Arg217ProfsTer8 variant is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000153783	SCV003807085	pathogenic	Infantile convulsions and choreoathetosis	2022-12-30	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PM6 moderated, PP1 strong, BS1 strong
Pediatrics, Sichuan Provincial Hospital For Women And Children	RCV000585818	SCV003842214	pathogenic	Seizures, benign familial infantile, 2	2023-02-16	criteria provided, single submitter	research	The proband, a male, 9 months old, There was no obvious cause before the onset of convulsion, the form of Generalized tonic-clonic seizures (GTCS), which occurred about 1-2 minutes after spontaneous stop.His mother and grandfather had the same seizure up to the age of six years old, after which they healed
Lifecell International Pvt. Ltd	RCV000153783	SCV003842254	pathogenic	Infantile convulsions and choreoathetosis		criteria provided, single submitter	clinical testing	A Heterozygous Frameshift variant c.640_641insC in Exon 2 of the PRRT2 gene that results in the amino acid substitution p.Arg217fs*8 was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (Variant ID: 65758). This variant has been identified in patients with infantile choreoathetosis and paroxysmal kinesigenic dyskinesia (Chen WJ et al., 2011). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000055991	SCV004020389	pathogenic	Episodic kinesigenic dyskinesia 1	2023-06-15	criteria provided, single submitter	clinical testing	Variant summary: PRRT2 c.649dupC (p.Arg217ProfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0037 in 135540 control chromosomes, however this information is unreliable due to low quality metrics at this position as indicated by analysis filters incorporated in gnomAD. c.649dupC has been reported in the literature in multiple individuals affected with PRRT2-related conditions (e.g., Ji_2021). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that approximately 80% of mutated transcripts are degraded by nonsense-mediated decay and residual mutated transcripts yield an N-terminally truncated protein (e.g., Wu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 33661484, 25457817). 39 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000153783	SCV004042676	pathogenic	Infantile convulsions and choreoathetosis		criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335084	SCV004046274	pathogenic	PRRT2-Related Disorders		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 2 of 3 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant is a recurrent cause of benign familial infantile epilepsy, infantile convulsions and choreoathetosis, and paroxysmal kinesigenic dyskinesia (PMID: 23299620, 22101681, 22870186, 22877996, 25667652). The c.649dup (p.Arg217ProfsTer8) variant is present in the gnomAD population database at a frequency of 0.3% (514/165666); however, quality metrics indicate the frequency data for this variant in the population databases is considered unreliable in the gnomAD database. Based on the available evidence, the c.649dup (p.Arg217ProfsTer8) variant is classified as Pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000055991	SCV004046802	pathogenic	Episodic kinesigenic dyskinesia 1		criteria provided, single submitter	not provided
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000153783	SCV004101501	pathogenic	Infantile convulsions and choreoathetosis		criteria provided, single submitter	clinical testing	The frameshift c.649dup (p.Arg217ProfsTer8) variant has been reported previously in heterozygous state in patients affected with Convulsions, familial infantile, with paroxysmal choreoathetosis (Swoboda KJ. et. al., 2000; Lee HY et. al., 2012).This position has been reported to be a mutational hotspot (Mao CY et. al., 2014) and as such, this variant is considered one of the most common, recurrent causes of both PKD and benign familial infantile seizures (Steinlein OK et. al., 2012; Becker F et. al., 2013). The p.Arg217ProfsTer8 variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.4% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This mutation creates a premature translational stop signal (p.Arg217Profs*8) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRRT2 are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003952479	SCV004774144	pathogenic	PRRT2-related condition	2023-11-17	criteria provided, single submitter	clinical testing	The PRRT2 c.649dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg217Profs*8). This variant has previously been reported to be causative for a broad range of autosomal dominant PRRT2-related phenotypes such as paroxysmal kinesigenic dyskinesia, familial hemiplegic migraine, benign familial infantile epilepsy (BFIE), and paroxysmal torticollis (Chen et al. 2011. PubMed ID: 22101681; Li et al. 2013. PubMed ID: 23535490; Ebrahimi-Fakhari et al. 2015. PubMed ID: 26598493; Zhao et al. 2018. PubMed ID: 29285950). In addition to variable expressivity, reduced penetrance is also documented for this gene (Ebrahimi-Fakhari et al. 1993. PubMed ID: 29334453). The c.649dup is the most common pathogenic variant reported in the PRRT2 gene. Note that allele frequency estimates at this position in the gnomAD public population database may be inaccurate (https://gnomad.broadinstitute.org). In summary, we classify this variant as pathogenic.
OMIM	RCV000055991	SCV000045455	pathogenic	Episodic kinesigenic dyskinesia 1	2012-10-01	no assertion criteria provided	literature only
OMIM	RCV000153783	SCV000045456	pathogenic	Infantile convulsions and choreoathetosis	2012-10-01	no assertion criteria provided	literature only
OMIM	RCV000585818	SCV000045457	pathogenic	Seizures, benign familial infantile, 2	2012-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000055991	SCV000087045	not provided	Episodic kinesigenic dyskinesia 1		no assertion provided	literature only
Baylor Genetics	RCV000055991	SCV000328734	pathogenic	Episodic kinesigenic dyskinesia 1	2016-05-01	no assertion criteria provided	clinical testing	Our laboratory reported two molecular diagnoses in KCNQ2 (NM_172108.4, c.2332delC) and PRRT2 (NM_145239.2, c.649dup) in an individual with Ohtahara syndrome, severe developmental delay, seizure disorder, structural brain anomalies and eye anomalies, severe hypotonia, bilateral hearing loss, and dysmorphic features.
GeneReviews	RCV000153783	SCV000747727	not provided	Infantile convulsions and choreoathetosis		no assertion provided	literature only
GeneReviews	RCV000585818	SCV000747728	not provided	Seizures, benign familial infantile, 2		no assertion provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000585818	SCV001469261	pathogenic	Seizures, benign familial infantile, 2	2020-06-07	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000188779	SCV001807268	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000188779	SCV001931576	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000585818	SCV002011753	pathogenic	Seizures, benign familial infantile, 2	2021-06-21	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000153783	SCV002029206	pathogenic	Infantile convulsions and choreoathetosis	2021-10-25	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000188779	SCV002036777	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000055991	SCV002583481	pathogenic	Episodic kinesigenic dyskinesia 1	2022-06-02	no assertion criteria provided	clinical testing