ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.4069G>C (p.Asp1357His) (rs193922626)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030422 SCV000053091 likely pathogenic Cardiomyopathy 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154818 SCV000204499 uncertain significance not specified 2019-01-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp1357His variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/8254 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs193922626). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of the Asp1357His variant.
Illumina Clinical Services Laboratory,Illumina RCV001097193 SCV001253451 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-01-13 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001097194 SCV001253452 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2018-01-13 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Health, Inc RCV000030422 SCV001341209 uncertain significance Cardiomyopathy 2020-11-12 criteria provided, single submitter clinical testing This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 15/279946 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.
Invitae RCV001372049 SCV001568637 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 1357 of the RYR2 protein (p.Asp1357His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs193922626, ExAC 0.01%). This variant has been observed in individual(s) with sudden unexplained death (PMID: 28807990). ClinVar contains an entry for this variant (Variation ID: 36743). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C). 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. 5

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