ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg350Trp i n DES gene has been reported in 1 55 year old individual with DCM (Taylor 2007). This variant has also been identified in 1/8600 European American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS; dbSNP rs62636492). This could represent a presymptomatic individ ual and the overall low population frequency supports pathogenicity. In vitro st udies showed disruption of the desmin filament assembly, although in vitro assay s do not always accurately reflect biological function (Taylor 2007). Arginine ( Arg) at position 350 is highly conserved evolution and computational analyses (b iochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that t his variant may impact the protein (the accuracy of these tools is unknown). Fin ally, another variant at this position (Arg350Pro) has been reported as a pathog enic variant in individuals with conduction system disease, and cardiac and skel etal myopathy (Bar 2005, Walter 2007, Levin 2010). In summary, the available dat a supports that the Arg350Trp variant may be pathogenic, though additional studi es are needed to fully assess its clinical significance.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest that desmin protein harboring p.(R350W) results in disruption of desmin filament assembly (Taylor et al., 2007); This variant is associated with the following publications: (PMID: 17439987, 27896284, 29247119, 23299917, 17325244, 20474083, 20448486, 15800015, 22337857, 29926427, 31514951, 28416588, 33500567, 31983221, 32150461, 29386531)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 350 of the DES protein (p.Arg350Trp). This variant is present in population databases (rs62636492, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 17325244, 29247119, 29386531; Invitae). ClinVar contains an entry for this variant (Variation ID: 44244). 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) performed at Invitae indicates that this missense variant is expected to disrupt DES protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DES function (PMID: 17325244). This variant disrupts the p.Arg350 amino acid residue in DES. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15800015, 17439987, 20448486, 25394388, 27393313). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This sequence change in DES is predicted to replace arginine with tryptophan at codon 350, p.(Arg350Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the intermediate filament (IF) rod domain. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.002% (25/1,180,008 alleles) in the European (non-Finnish) population, which is consistent with dilated cardiomyopathy. This variant has been reported in at least seven unrelated individuals with dilated cardiomyopathy (PMID: 17325244, 28416588, 29386531, 31983221, 33823640; ClinVar: SCV000206887.1, SCV001203482.4). An in vitro functional assay with limited validation in neonatal rat myocytes showed that the formation of desmin filaments was affected in the presence of the variant indicating that it impacts protein function (PMID: 17325244). Computational evidence predicts a deleterious effect for the missense substitution (REVEL =0.853). Another missense variant c.1049G>C, p.(Arg350Pro) in the same codon has been classified as pathogenic for DES-related myofibrillar myopathy (ClinVar ID: 16835; PMID: 25394388, 15800015). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PM5, PP3, PS3_Supporting, PS4_Moderate

The c.1048C>T (p.R350W) alteration is located in exon 6 (coding exon 6) of the DES gene. This alteration results from a C to T substitution at nucleotide position 1048, causing the arginine (R) at amino acid position 350 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

The DES c.1048C>T variant is predicted to result in the amino acid substitution p.Arg350Trp. This variant was reported in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, left ventricular noncompaction, or sudden unexplained deaths (Taylor et al. 2007. PubMed ID: 17325244; Table S3, Lin et al. 2017. PubMed ID: 29247119; Online Table 1, Gigli et al. 2019. PubMed ID: 31514951; Table S1, Hoss et al. 2020. PubMed ID: 32150461; Table S2, Mazzarotto et al. 2021. PubMed ID: 33500567). Functional studies suggested that this variant could disrupt the intracytoplasmic localization (Taylor et al. 2007. PubMed ID: 17325244). However, this variant was also documented in the general population (Andreasen et al. 2013. PubMed ID: 23299917; Table S1, Nouhravesh et al. 2016. PubMed ID: 27896284). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain significance to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/44244). A different nucleotide substitution affecting the same amino acid (p.Arg350Pro) has been reported to be causative for DES-associated disorders (Bar et al. 2005. PubMed ID: 15800015; Walter et al. 2007. PubMed ID: 17439987). Although we suspect that the c.1048C>T (p.Arg350Trp) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.