Submissions for variant NM_145239.3(PRRT2):c.604_607del (p.Ser202fs)

dbSNP: rs1064793851

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485009	SCV000567183	pathogenic	not provided	2020-03-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Liu et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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; This variant is associated with the following publications: (PMID: 26598493, 23299620, 23360469, 27172900, 29655203, 25403460, 22870186, 31164858, 31722684)
Invitae	RCV000802861	SCV000942707	pathogenic	Episodic kinesigenic dyskinesia	2022-09-13	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individuals with paroxysmal kinesigenic dyskinesia with infantile convulsions and benign familial infantile seizures (BFIS) (PMID: 22870186, 23360469, 25403460). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser202Hisfs*26) 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). ClinVar contains an entry for this variant (Variation ID: 419406). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002356774	SCV002656723	pathogenic	Inborn genetic diseases	2017-07-17	criteria provided, single submitter	clinical testing	The c.604_607delTCAC pathogenic mutation, located in coding exon 1 of the PRRT2 gene, results from a deletion of 4 nucleotides at nucleotide positions 604 to 607, causing a translational frameshift with a predicted alternate stop codon (p.S202Hfs*26). This mutation has been detected in multiple individuals with paroxysmal kinesigenic dyskinesia, benign family infantile seizures, and choreoathetosis (Lee YC et al. PLoS ONE, 2012 Aug;7:e38543; Zara F et al. Epilepsia, 2013 Mar;54:425-36; Zhang LM et al. J. Child Neurol., 2015 Sep;30:1263-9). In addition, in one functional study, authors showed that this mutation accumulated in the cytoplasm and thus failed to target to the cell membrane (Liu YT et al. Oncotarget, 2016 Jun;7:39184-39196). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000485009	SCV004702880	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PRRT2: PVS1, PP1:Strong, PM2, PS4:Moderate, PS3:Supporting