ClinVar Genomic variation as it relates to human health

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 451 of the DES protein (p.Ile451Met). This variant is present in population databases (rs121913002, gnomAD 0.02%). This missense change has been observed in individual(s) with DES-related conditions (PMID: 10430757, 10717012, 11728149, 30403391, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16824). 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: 17105773, 17221859, 18539904, 28470624). 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.

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). 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.

Variant summary: DES c.1353C>G (p.Ile451Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 233386 control chromosomes. The observed variant frequency is approximately 2.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.1353C>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (DCM) (example, Li_1999, Miyamoto_2001, van Lint_2019), in unaffected family members (example, Li_1999, Dalakas_2003), and individuals with skeletal myopathy without DCM (example, Dalakas_2000, Dalakas_2003). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Dalakas_2003, Mavrodis_2008). One study reported that this variant was functional and normally interacted with other intermediate filaments (Dalakas_2003) while another reported that mutant desmin loses its Z-disc localization but it can still associate with the intercalated discs, which, however, have an altered architecture, resembling other examples of dilated cardiomyopathy (Mavrodis_2008). These results however, do not allow convincing conclusions about the variant effect. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

Reported in association with DCM and HCM, and was shown to segregate with disease in one affected relative from a single family; however, only the DES gene was analyzed in this family (Li et al., 1999; van Lint et al., 2019; Oktay et al., 2023); Identified in three affected relatives from one family with skeletal myopathy; however, only the DES gene was analyzed in these individuals (Dalakas et al., 2003).; Functional studies have been inconsistent in demonstrating a damaging effect (Lapouge et al., 2006; Mavroidis et al., 2008; Sharma et al., 2017; Dalakas et al., 2003; Bar et al., 2007; Chourbagi et al., 2011).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36935760, 16761416, 11052860, 21262226, 17221859, 28470624, 18539904, 16979163, 30403391, 26807690, 30847666, 11728149, 37466024, 12609507, 17105773, 10430757)

The c.1353C>G (p.I451M) alteration is located in exon 8 (coding exon 8) of the DES gene. This alteration results from a C to G substitution at nucleotide position 1353, causing the isoleucine (I) at amino acid position 451 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.