ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.

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)

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). ClinVar contains an entry for this variant (Variation ID: 44274). Advanced 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 at Invitae 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.

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.