The c.937G>A p.(Ala313Thr) variant identified in the DES gene has not previously been reported in the literature and has been deposited in ClinVar [ClinVar ID: 228553] as Variant of Uncertain Significance. The c.937G>A variant is observed in 9 alleles (~0.002% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.937G>A variant in DES is located in exon 5 of this 9-exon gene, and predicted to replace an evolutionarily conserved alanine amino acid with threonine at position 313 in the region of interaction with NEB of the encoded protein. In silico predictions are in favor of damaging effect for p.(Ala313Thr) [(CADD v1.6= 34, REVEL = 0.686)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.937G>Ap.(Ala313Thr) variant identified in DES is classified as a Variant of Uncertain Significance.

The p.A313T variant (also known as c.937G>A), located in coding exon 5 of the DES gene, results from a G to A substitution at nucleotide position 937. The alanine at codon 313 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD)

The p.Ala313Thr variant in DES has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 3/66414 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In summary, the clinical significance of the p.Ala313Thr variant is uncertain.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 313 of the DES protein (p.Ala313Thr). This variant is present in population databases (rs766252091, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 228553). 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. 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.