ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9655G>A (p.Val3219Met) (rs371147744)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210635 SCV000263004 likely benign Inborn genetic diseases 2014-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768781 SCV000900151 uncertain significance Cardiomyopathy 2017-08-24 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000590419 SCV000697635 likely benign not provided 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.9655G>A (p.Val3219Met) variant involves the alteration of a non-conserved nucleotide, which is not located in any known domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 9/120608 control chromosomes at a frequency of 0.0000746, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000025), suggesting this variant is likely a benign polymorphism. However, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.
Invitae RCV000559506 SCV000637635 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 3219 of the RYR2 protein (p.Val3219Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs371147744, ExAC 0.03%). This variant has been reported in the literature in individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) or referred for genetic testing (PMID: 25041964, 28404607). ClinVar contains an entry for this variant (Variation ID: 201179). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare 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.
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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