ClinVar Genomic variation as it relates to human health

ACMG score pathogenic

The Arg454Trp variant in DES has been identified in 1 individual with HCM and mu scle weakness and in 2 siblings with AV Block and cardiac hypertrophy that progr essed to heart failure (Bar 2007, Otten 2010). This variant was also absent from 600 chromosomes and reportedly occurred de novo in the individual with HCM (Bar 2007). Functional studies demonstrated an effect on filament formation (Bar 200 7, Levin 2010). Arginine (Arg) at position 454 is highly conserved in evolution and computational analyses (PolyPhen2 and SIFT) suggest that this variant may im pact the protein, though this information is not predictive enough to determine a pathogenic role. Desmin variants have been described in patients with cardiomy opathy +/- myopathy (desminopathies; Goldfarb 2009, van Spaendonck-Zwarts 2010). In summary, this data supports that the Arg454Trp variant is likely pathogenic, though is needed to fully establish its pathogenicity.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 454 of the DES protein (p.Arg454Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant DES-related conditions (PMID: 17221859, 20423733, 22106715, 22153487, 23349452, 25557463, 27854218). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66402). 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: 17221859, 20171226, 20448486). For these reasons, this variant has been classified as Pathogenic.

The p.R454W pathogenic mutation (also known as c.1360C>T), located in coding exon 8 of the DES gene, results from a C to T substitution at nucleotide position 1360. The arginine at codon 454 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the tail domain. This alteration was first reported in a subject with suspected hypertrophic cardiomyopathy (HCM) and muscle weakness who also carried a missense alteration in MYOT (Bär H et al. Hum Mutat, 2007 Apr;28:374-86). This alteration has also been reported in 2 sets of siblings with arrhythmogenic right ventricular cardiomyopathy (ARVC), including one set who also had muscle weakness (Otten E et al. Heart Rhythm, 2010 Aug;7:1058-64; Weihl CC et al. Neuromuscul Disord, 2015 Mar;25:199-206). In addition, this alteration has been reported as de novo in several cases (Bär H et al. Hum Mutat, 2007 Apr;28:374-86; Ackerman JP et al. Mayo Clin Proc, 2016 Oct; Oomen AWGJ et al. HeartRhythm Case Rep, 2018 Jul;4:318-323; Gearhart AS et al. HeartRhythm Case Rep, 2018 May;4:184-186). Functional studies also suggest this alteration has an impact on filament formation (Bär H et al. Hum Mutat, 2007 Apr;28:374-86; Levin J et al. J Neuropathol Exp Neurol, 2010 Apr;69:415-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

A heterozygous missense variation in exon 8 of the DES gene that results in the amino acid substitution of Tryptophan for Arginine at codon 454 was detected . The observed variation has previously been reported in patients affected with myofibrillar myopathy. The p.Arg454Trp variant has not been reported in 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT. The reference codon is conserved across species. This variant has been previously reported in patients with early distal myopathy and cardiomyopathy (PMID: 37082475). In summary, the variant meets our criteria to be classified as pathogenic.

Reported in ClinVar as a pathogenic and likely pathogenic variant (ClinVar Variant ID# 66402; Landrum et al., 2016); Immunohistochemistry on myocardial samples showed severely disrupted desmin protein distribution and a marked decrease in connexin-43, desmoplakin, and PKP2 signals at the intercalated discs (Otten et al., 2010); 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: 23349452, 20448486, 25557463, 20423733, 25179549, 22403400, 17221859, 27854218, 22153487, 22106715, 18769253, 27810088, 28256728, 29915714, 28611029, 30023281, 28986455, 31912959, 32142595, 31737537, 31402444, 33673806, 32528171)