Submissions for variant NM_001927.4(DES):c.1048C>T (p.Arg350Trp)

gnomAD frequency: 0.00002  dbSNP: rs62636492

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037224	SCV000060881	uncertain significance	not specified	2012-09-05	criteria provided, single submitter	clinical testing	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.
Invitae	RCV001039932	SCV001203482	pathogenic	Desmin-related myofibrillar myopathy	2023-12-25	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000056766	SCV002549512	uncertain significance	not provided	2022-07-13	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000056766	SCV003829004	uncertain significance	not provided	2020-11-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298065	SCV003995335	uncertain significance	Cardiovascular phenotype	2023-04-14	criteria provided, single submitter	clinical testing	The p.R350W variant (also known as c.1048C>T), located in coding exon 6 of the DES gene, results from a C to T substitution at nucleotide position 1048. The arginine at codon 350 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the coil 2B region of the rod domain. This alteration was initially detected in an individual with dilated cardiomyopathy (DCM), and in vitro studies suggested this variant may alter protein function; however, the physiologic relevance of the observed findings is unclear (Taylor MR et al. Circulation, 2007 Mar;115:1244-51). This variant has also been detected in additional DCM cases, a hypertrophic cardiomyopathy (HCM) cohort, a left ventricular non-compaction (LVNC) genetic testing cohort, a sudden death cohort, and an exome cohort; however clinical details were limited for these individuals (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10; Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Tobita T et al. Sci Rep, 2018 01;8:1998; Hoss S et al. Circ Genom Precis Med, 2020 04;13:e002748; Mazzarotto F et al. Circulation, 2020 02;141:387-398; Mazzarotto F et al. Genet Med, 2021 05;23:856-864). Other variants affecting this codon (p.R350P and p.R350Q) have been reported in association with skeletal myopathy and cardiomyopathy (Bär H et al. Hum. Mol. Genet., 2005 May;14:1251-60; Shanks GW et al. Circulation, 2018 Jun;137:2705-2715). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003398603	SCV004103509	uncertain significance	DES-related condition	2024-01-24	criteria provided, single submitter	clinical testing	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486560	SCV004240479	uncertain significance	Cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056766	SCV000087879	not provided	not provided		no assertion provided	not provided
Blueprint Genetics	RCV000157164	SCV000206887	likely pathogenic	Primary dilated cardiomyopathy	2014-09-29	no assertion criteria provided	clinical testing
OMIM	RCV001250885	SCV001426378	pathogenic	Dilated cardiomyopathy 1I	2007-03-13	no assertion criteria provided	literature only