ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4735G>A (p.Val1579Met)

gnomAD frequency: 0.00008  dbSNP: rs763389778
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001181794 SCV001347020 uncertain significance Cardiomyopathy 2022-12-06 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 1579 of 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 17/276474 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192693 SCV001360975 likely benign not specified 2021-04-20 criteria provided, single submitter clinical testing Variant summary: RYR2 c.4735G>A (p.Val1579Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 389770 control chromosomes, predominantly at a frequency of 0.00025 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3 dataset). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.4735G>A has been reported in the literature in a whole exome sequencing cohort without specific phenotypic information provided (Landstrom_2017). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV002559005 SCV001489247 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-16 criteria provided, single submitter clinical testing
GeneDx RCV001593312 SCV001816704 uncertain significance not provided 2022-04-11 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 19926015)
Ambry Genetics RCV002560813 SCV003737723 uncertain significance Inborn genetic diseases 2022-03-21 criteria provided, single submitter clinical testing The c.4735G>A (p.V1579M) alteration is located in exon 36 (coding exon 36) of the RYR2 gene. This alteration results from a G to A substitution at nucleotide position 4735, causing the valine (V) at amino acid position 1579 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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