ClinVar Miner

Submissions for variant NM_145239.3(PRRT2):c.649dup (p.Arg217fs) (rs587778771)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188779 SCV000203360 pathogenic not provided 2014-04-29 criteria provided, single submitter clinical testing
GeneDx RCV000188779 SCV000242403 pathogenic not provided 2018-10-25 criteria provided, single submitter clinical testing The c.649dupC variant is a recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenic alleles in the PRRT2 gene. It has been identified in individuals from a variety of ethnic backgrounds with paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), benign familial infantile seizures (BFIS), and isolated PKD (Chen et al., 2011; Meneret et al., 2012; Lee YC et al., 2012; Schubert et al., 2012). This duplication causes a frameshift starting with codon Arginine 217, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Arg217ProfsX8. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, the presence of c.649dupC is consistent with a diagnosis of a PRRT2-related disorder in this individual.
Genetic Services Laboratory, University of Chicago RCV000193894 SCV000248604 pathogenic Seizures 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 Paroxysmal kinesigenic dyskinesia 2019-01-05 criteria provided, single submitter clinical testing 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. This particular variant has been reported in the literature in many sporadic and familial cases of paroxysmal kinesigenic dyskinesia (PKD) and/or infantile seizures (PMID: 22101681, 22870186, 22877996, 25667652). In the familial cases, co-segregation with disease has been reported. This position has been reported to be a mutational hotspot (PMID: 24661410) and as such, this variant is considered one of the most common, recurrent causes of both PKD and benign familial infantile seizures (PMID: 22877996, 23299620). 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 2016-08-30 criteria provided, single submitter clinical testing
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 RCV000718212 SCV000849074 pathogenic History of neurodevelopmental disorder 2018-04-20 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses);Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768059 SCV000898913 pathogenic Seizures, benign familial infantile, 2; Dystonia 10; Infantile convulsions and paroxysmal choreoathetosis, familial 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 Dystonia 10 2019-05-28 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health: University of Minnesota RCV000991298 SCV001142699 pathogenic Paroxysmal nonkinesigenic dyskinesia 1 2019-06-17 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000585818 SCV001149892 pathogenic Seizures, benign familial infantile, 2 2019-08-08 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 Dystonia 10 2018-03-02 criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV000153783 SCV001167610 pathogenic Infantile convulsions and paroxysmal choreoathetosis, familial 2018-09-06 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000153783 SCV001192520 pathogenic Infantile convulsions and paroxysmal choreoathetosis, familial 2019-11-13 criteria provided, single submitter research ACMG codes: PVS1, PM1, PP1, PP5
OMIM RCV000055991 SCV000045455 pathogenic Dystonia 10 2012-10-01 no assertion criteria provided literature only
OMIM RCV000153783 SCV000045456 pathogenic Infantile convulsions and paroxysmal choreoathetosis, familial 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 pathogenic Dystonia 10 2017-11-06 no assertion criteria provided literature only
Baylor Genetics RCV000055991 SCV000328734 pathogenic Dystonia 10 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 pathogenic Infantile convulsions and paroxysmal choreoathetosis, familial 2017-11-06 no assertion criteria provided literature only
GeneReviews RCV000585818 SCV000747728 pathogenic Seizures, benign familial infantile, 2 2017-11-06 no assertion criteria provided literature only

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