Submissions for variant NM_001927.4(DES):c.935A>C (p.Asp312Ala)

gnomAD frequency: 0.00093  dbSNP: rs148947510

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037258	SCV000060915	likely benign	not specified	2012-03-02	criteria provided, single submitter	clinical testing	p.Asp312Ala in exon 5 of DES: This variant is not expected to have clinical sign ificance because it has been identified in 0.3% (11/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs148947510).
GeneDx	RCV000725547	SCV000235785	uncertain significance	not provided	2024-07-25	criteria provided, single submitter	clinical testing	Identified in individuals with HCM, DCM, or sudden unexplained death in published literature; however, several individuals harbored additional cardiogenetic variants (PMID: 23785128, 24503780, 27930701, 30847666); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 27930701, 29926427, 17325244, 30847666, 26807690, 23785128, 34935411)
Ambry Genetics	RCV000243219	SCV000319576	likely benign	Cardiovascular phenotype	2020-10-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000725547	SCV000337681	uncertain significance	not provided	2017-11-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085666	SCV000562348	likely benign	Desmin-related myofibrillar myopathy	2025-01-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000725547	SCV001475075	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is damaging.
Revvity Omics, Revvity	RCV000725547	SCV003829031	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037258	SCV005883031	likely benign	not specified	2024-12-27	criteria provided, single submitter	clinical testing	Variant summary: DES c.935A>C (p.Asp312Ala) results in a non-conservative amino acid change located in the Intermediate filament (IF) rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251070 control chromosomes, predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Autosomal Recessive Desminopathy phenotype (0.0025). c.935A>C has been reported in the literature in individuals affected with cardiomyopathy or cases of sudden unexplained death without evidence for causality (e.g. Mook_2013, Pugh_2014, Khan_2022, Sahnchez_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Desminopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34935411, 23785128, 24503780, 27930701). ClinVar contains an entry for this variant (Variation ID: 44275). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003914934	SCV004732230	likely benign	DES-related disorder	2022-09-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).