ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9655G>A (p.Val3219Met)

gnomAD frequency: 0.00011  dbSNP: rs371147744
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590419 SCV000235014 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The V3219M variant has previously been reported in a 41 year-old patient who had clinical features consistent with ARVC, but did not meet 2010 Task Force Criteria for a diagnosis of ARVC (Roux-Buisson et al., 2014). This variant has also been observed in other unrelated individuals referred for cardiac genetic testing at GeneDx, and has been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000263004.2, SCV000272400.1, SCV000280458.1; Landrum et al., 2016). The V3219M variant was not observed at a significant frequency in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the V3219M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and Methionine is the wild-type amino acid at this position in at least two species. This variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Furthermore, 2/3 in silico splice prediction programs predict this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics RCV000210635 SCV000263004 uncertain significance Inborn genetic diseases 2018-02-16 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000216905 SCV000272400 uncertain significance not specified 2015-12-03 criteria provided, single submitter clinical testing The p.Val3219Met variant in RYR2 has been reported in 1 individual with ARVC (Ro ux-Buisson 2014) and in 5/66632 European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rrs371147744). Computatio nal prediction tools and conservation analysis suggest that the p.Val3219Met var iant may not impact the protein, though this information is not predictive enoug h to rule out pathogenicity. In summary, the clinical significance of the p.Val3 219Met variant is uncertain.
Invitae RCV001099558 SCV000637635 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000216905 SCV000697635 likely benign not specified 2023-04-18 criteria provided, single submitter clinical testing Variant summary: RYR2 c.9655G>A (p.Val3219Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249136 control chromosomes (gnomAD). The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.9655G>A has been reported in the literature in individuals affected with presyncope and myocarditis (example: Roux-Buisson_2014 and Seidel_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000768781 SCV000900151 uncertain significance Cardiomyopathy 2017-08-24 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001099558 SCV001256023 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina RCV001099559 SCV001256024 uncertain significance Arrhythmogenic right ventricular dysplasia 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health RCV000768781 SCV001348915 uncertain significance Cardiomyopathy 2023-02-06 criteria provided, single submitter clinical testing This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 21/280528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002372115 SCV002689117 uncertain significance Cardiovascular phenotype 2022-03-31 criteria provided, single submitter clinical testing The p.V3219M variant (also known as c.9655G>A), located in coding exon 68 of the RYR2 gene, results from a G to A substitution at nucleotide position 9655. The valine at codon 3219 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a cohort of subjects referred for arrhythmogenic right ventricular cardiomyopathy (ARVC) genetic testing (Roux-Buisson N et al. Heart Rhythm, 2014 Nov;11:1999-2009). This alteration has also been reported in an exome cohort, but cardiovascular history was not provided (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen RCV000590419 SCV004033017 likely benign not provided 2023-08-01 criteria provided, single submitter clinical testing RYR2: BP4
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000216905 SCV000280458 uncertain significance not specified 2011-03-31 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val3219Met (V3219M; c.9655 G>A) in the RYR2 gene: Based on the limited data currently available about this variant (reviewed in detail below), we agree and consider this a variant of unknown significance. This variant has been reported just once in the literature, according to our search, by Roux-Buisson et al. (online publication before print, July 2014). No segregation data is available. They found this variant in one Caucasian male proband recruited in France or Switzerland who was borderline for ARVC by 2010 criteria and who had previously tested negative for variants in desmosomal genes associated with ARVC (PKP2, DSG2, DSP, JUP, and DSC2). This was a sporadic case, with no family history of ARVC, who presented with presyncope at the age of 41. Resting EKG showed T wave inversion from lead V1 to lead V3. 24-hour Holter monitoring detected frequent monomorphic ventricular ectopies decreasing during exercise. Cardiac imaging showed wall motion abnormalities with dyskinesia and RV aneurysm but no RV dilatation and therefore did not reach the 2010 diagnostic criteria. This is a conservative amino acid substitution from a nonpolar valine to a nonpolar methionine at a residue that is not conserved across vertebrate species (Ambry lists at least 7 species it differs in including rat and mouse). This valine is not conserved across paralog proteins (RYR1-RYR3; http://cardiodb.org/Paralogue_Annotation/), and nor are several amino acids nearby. In silico analysis with PolyPhen-2 predicts this variant to be “Possibly Damaging” with a score of 0.631. SIFT predicts that it is tolerated, according to Ambry. Yano et al. (2006) reported that disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959). This variant does not fall within a known disease-causing hotspot. There are no missense variants at nearby residues (+/-10) listed in HGMD in association with CPVT or ARVC (as of January 2014). This variant is listed in dbSNP as rs371147744. It was submitted twice: Once by the NHLBI ESP, and once by a genome sequencing project in the Netherlands. The variant has been seen in 1 out of ~6,200 individuals from controls and individuals from publicly available population datasets. Of note, none of these match the ethnicity of our patients, which is Filipino. It is present in one Caucasian from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Roux-Buisson et al. (2014) did not find it in 200 Caucasian controls. There is no variation at this codon listed in 1000 Genomes (as of November 10, 2014).

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