Submissions for variant NM_145239.3(PRRT2):c.971del (p.Gly324fs)

dbSNP: rs796052941

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188780	SCV000242404	likely pathogenic	not provided	2015-11-06	criteria provided, single submitter	clinical testing	The c.971delG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.971delG variant causes a frameshift starting with codon Glycine 324, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Gly324GlufsX13. This variant is predicted to cause loss of normal protein function through protein truncation as the last 17 amino acids of the PRRT2 protein are lost and replaced by 12 incorrect amino acids. Although this variant has not been previously reported to our knowledge, other frameshift variants have been reported in the Human Gene Mutation Database in association with PRRT2-related disorders (Stenson et al., 2014).
Invitae	RCV000544016	SCV000645436	pathogenic	Episodic kinesigenic dyskinesia	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly324Glufs*13) in the PRRT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PRRT2 protein. This variant is present in population databases (rs796052941, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with PRRT2-related conditions (PMID: 30386286). ClinVar contains an entry for this variant (Variation ID: 206696). This variant disrupts a region of the PRRT2 protein in which other variant(s) (p.Ile327Met) have been determined to be pathogenic (PMID: 2131349, 23496026, 24609974, 24886244). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV002247606	SCV002518925	pathogenic	Episodic kinesigenic dyskinesia 1	2022-05-04	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002510567	SCV002820260	pathogenic	Seizures, benign familial infantile, 2		criteria provided, single submitter	clinical testing	The frameshift deletion p.G324Efs*13 in PRRT2 (NM_145239.2) has been observed before in a patient with paroxysmal kinesigenic dyskinesia (Liu YT et al). It has been submitted to ClinVar as Likely Pathogenic. Other missense variants occuring at this residue have been deemed to be disease causing (Tsai MH et al). The p.G324Efs*13 variant is novel not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 13 residues until a stop codon is reached. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000188780	SCV004033475	likely pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	PRRT2: PM2, PS4:Moderate, PVS1:Moderate, PP4