Submissions for variant NM_145239.3(PRRT2):c.649C>T (p.Arg217Ter)

dbSNP: rs77838305

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554439	SCV000645431	pathogenic	Episodic kinesigenic dyskinesia	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 468617). This premature translational stop signal has been observed in individuals with paroxysmal kinesigenic dyskinesia, and infantile convulsions and paroxysmal choreoathetosis (PMID: 22464846, 22744660, 22752065, 22902309, 23363396, 28074849). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg217*) 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).
Baylor Genetics	RCV001332953	SCV001525399	pathogenic	Infantile convulsions and choreoathetosis	2020-01-20	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001545693	SCV001765073	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25340963, 28074849, 22464846, 22902309, 23551744, 22744660, 23363396, 24370076, 22752065, 29285950, 29655203, 32651081)
MGZ Medical Genetics Center	RCV002289762	SCV002581869	pathogenic	Seizures, benign familial infantile, 2	2022-08-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001545693	SCV004033474	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PRRT2: PVS1, PM2, PP1:Moderate, PS4:Moderate, PS3:Supporting
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787889	SCV005398960	pathogenic	PRRT2-associated paroxysmal movement disorder	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in a family with PRRT2-related symptoms (PMID: 28074849). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001545693	SCV002034237	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001545693	SCV002035216	pathogenic	not provided		no assertion criteria provided	clinical testing