ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188778 SCV000242402 pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing The c.649delC pathogenic variant in the PRRT2 gene has been reported previously in multiple unrelated individualswith PRRT2-related disorders (Meneret et al., 2012; Yang et al., 2013). This deletion causes a frameshift starting with codon Arginine 217, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon atposition 12 of the new reading frame, denoted p.Arg217GlufsX12. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. A duplication at the same position (c.649dupC) is a recurrent pathogenic variant that accounts for approximately 77-93% of all pathogenicvariants in the PRRT2 gene, and other frameshift variants have been reported in association with PRRT2-related disorders (Stenson et al., 2014). Therefore, this result is consistent with a diagnosis of a PRRT2-related disorder in this individual.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188778 SCV000708571 pathogenic not provided 2017-05-22 criteria provided, single submitter clinical testing
Invitae RCV000820557 SCV000961274 pathogenic Paroxysmal kinesigenic dyskinesia 2020-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg217Glufs*12) in the PRRT2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to segregate with PRRT2-related conditions in families (PMID: 24755245, 24370076) and has been reported in individuals affected with paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, hemiplegic migraine, or Dravet syndrome (PMID: 22744660, 24370076, 23077016, 25522171). ClinVar contains an entry for this variant (Variation ID: 39752). A different truncation (p.Gly324Glufs*13) that lies downstream of this variant has been determined to be pathogenic (PMID: 22832103). This suggests that deletion of this region of the PRRT2 protein is causative of disease. Loss-of-function variants in PRRT2 are known to be pathogenic (PMID: 22623405, 22744660). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000032970 SCV001140083 likely pathogenic Episodic kinesigenic dyskinesia 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188778 SCV001248448 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253175 SCV001428758 pathogenic Seizures, benign familial infantile, 2 2019-11-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000032970 SCV001526179 pathogenic Episodic kinesigenic dyskinesia 1 2018-11-08 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID 22744660, 24755245, 25522171, 28906077, 27172900, 24370076, 25449067]
OMIM RCV000032970 SCV000056745 pathogenic Episodic kinesigenic dyskinesia 1 2012-07-10 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000188778 SCV001742025 pathogenic not provided no assertion criteria provided clinical testing

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