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

gnomAD frequency: 0.00010  dbSNP: rs193922626

Total submissions: 7

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, Mass General Brigham 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 Laboratory Services, Illumina	RCV001097193	SCV001253451	uncertain significance	Arrhythmogenic right ventricular dysplasia 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.
Color Diagnostics, LLC DBA Color Health	RCV000030422	SCV001341209	uncertain significance	Cardiomyopathy	2023-01-10	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001097194	SCV001568637	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1357 of the RYR2 protein (p.Asp1357His). This variant is present in population databases (rs193922626, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 28807990). ClinVar contains an entry for this variant (Variation ID: 36743). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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.
All of Us Research Program, National Institutes of Health	RCV003996140	SCV004817605	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-07-29	criteria provided, single submitter	clinical testing	This variant replaces aspartic acid with histidine at codon 1357 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.
Ambry Genetics	RCV004018690	SCV004945116	uncertain significance	Cardiovascular phenotype	2022-09-08	criteria provided, single submitter	clinical testing	The c.4069G>C (p.D1357H) alteration is located in exon 31 (coding exon 31) of the RYR2 gene. This alteration results from a G to C substitution at nucleotide position 4069, causing the aspartic acid (D) at amino acid position 1357 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.