Submissions for variant NM_001927.4(DES):c.934G>A (p.Asp312Asn)

gnomAD frequency: 0.00059  dbSNP: rs34337334

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000056815	SCV000060914	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing	The p.Asp312Asn variant in DES has been reported in 1 Black individual with DCM and in vitro studies suggest that this variant may impact protein function, though these assays may not accurately represent biological function (Taylor 2007). In addition, this variant has been identified by our laboratory in 1 Black individual with infant-onset complex cardiomyopathy a well as 2 members of a Hispanic family (both with DCM). However, this variant is present in 0.2% (7/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs34337334). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp312Asn variant is uncertain. ACMG/AMP criteria applied: BA1.
GeneDx	RCV000056815	SCV000235784	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Expression studies suggest this variant results in impairment of the desmin filament network (Taylor et al., 2007); however, it is unclear how these studies may translate to a pathogenic role in vivo; This variant is associated with the following publications: (PMID: 22337857, 27896284, 24503780, 23299917, 29988065, 32403337, 34426522, 17325244, 34045587)
Ambry Genetics	RCV000245347	SCV000318775	likely benign	Cardiovascular phenotype	2022-02-22	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)	RCV000056815	SCV000331799	uncertain significance	not provided	2018-02-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475003	SCV000552168	uncertain significance	Desmin-related myofibrillar myopathy	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 312 of the DES protein (p.Asp312Asn). This variant is present in population databases (rs34337334, gnomAD 0.2%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 17325244, 24503780, 37652022). ClinVar contains an entry for this variant (Variation ID: 44274). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. Experimental studies have shown that this missense change affects DES function (PMID: 17325244). 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.
Athena Diagnostics	RCV000056815	SCV000841808	uncertain significance	not provided	2017-09-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770171	SCV000901598	uncertain significance	Cardiomyopathy	2015-11-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000475003	SCV001136223	uncertain significance	Desmin-related myofibrillar myopathy	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000056815	SCV001153320	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001137622	SCV001297584	uncertain significance	Dilated cardiomyopathy 1I	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000475003	SCV001297585	uncertain significance	Desmin-related myofibrillar myopathy	2017-04-27	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 Laboratory Services, Illumina	RCV001137623	SCV001297587	benign	Neurogenic scapuloperoneal syndrome, Kaeser type	2017-04-27	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Genetics and Genomics Program, Sidra Medicine	RCV001293064	SCV001434046	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
New York Genome Center	RCV002265577	SCV002506743	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2021-05-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000056815	SCV003829010	uncertain significance	not provided	2019-07-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000056815	SCV005876609	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	The DES c.934G>A; p.Asp312Asn variant (rs34337334) is reported in the literature in multiple individuals affected with dilated cardiomyopathy, as well as one individual with symptoms of a neuromuscular disorder, although it was not demonstrated to be disease-causing in these individuals (Gonzalez-Quereda 2020, McGurk 2023, Taylor 2007). This variant is found in the African population with an allele frequency of 0.19% (48/24,928 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.521). Functional studies have noted altered subcellular localization compared to wildtype DES protein when expressed in cultured cells, but the functional significance of this assay is unclear (Taylor 2007). Due to limited and conflicting information, the clinical significance of the p.Asp312Asn variant is uncertain at this time. References: Gonzalez-Quereda L et al. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes (Basel). 2020 May 11;11(5):539. PMID: 32403337. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Taylor MR et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation. 2007 Mar 13;115(10):1244-51. PMID: 17325244.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056815	SCV000087928	not provided	not provided		no assertion provided	not provided