Submissions for variant NM_001927.4(DES):c.1216C>T (p.Arg406Trp)

dbSNP: rs121913003

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000056781	SCV000231642	pathogenic	not provided	2016-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000056781	SCV000235790	pathogenic	not provided	2023-04-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate abnormal filament assembly, in addition to microscopic analysis of cardiac and skeletal muscle revealing desmin-positive protein aggregates (Park et al., 2000; Chourbagi et al., 2011; Herrmann et al., 2020; Kubnek et al., 2020); 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: 10717012, 35653365, 35626289, 35239206, 26807690, 10905661, 14991347, 27854218, 33673806, 32528171, 34712946, 32235386, 21262226, 33023321, 16376610)
Center for Genetic Medicine Research, Children's National Medical Center	RCV000627795	SCV000265769	likely pathogenic	Desmin-related myofibrillar myopathy	2015-12-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000627795	SCV000271350	pathogenic	Desmin-related myofibrillar myopathy	2015-03-11	criteria provided, single submitter	clinical testing	The p.Arg406Trp variant in DES is absent from large populations sequenced by the Exome Aggregation Consortium (exac.broadinstitute.org/) but has been reported i n at least 5 individuals with clinical features of desminopathies, including con duction system disease +/-cardiomyopathy (DCM and RCM) and skeletal myopathy (sa me individuals reported in multiple papers; Dalakas 2000, Park 2000, Dagvadirj 2 004, Olive 2004, Wahbi 2012). In at least least 4 individuals the variant had oc curred de novo (paternity confirmed; same individuals reported in multiple paper s; Dalakas 2000, Park 2000, Dagvadirj 2004, Olive 2004). In vitro functional stu dies provide some evidence that the p.Arg406Trp variant impacts protein function (Park 2000, Chourbagi 2011). However, these types of assays sometimes do not ac curately represent biological function. In summary, this variant meets our crite ria to be classified as pathogenic for desminopathy with cardiac and skeletal my opathy involvement in an autosomal dominant manner (http://www.partners.org/pers onalizedmedicine/LMM) based upon absence from the general population and de novo occurrence.
Invitae	RCV000627795	SCV000552187	pathogenic	Desmin-related myofibrillar myopathy	2023-12-07	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 406 of the DES protein (p.Arg406Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with desmin myopathy (PMID: 10717012, 10905661, 14991347). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16826). 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: 21262226, 23425003). For these reasons, this variant has been classified as Pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000627795	SCV001149752	pathogenic	Desmin-related myofibrillar myopathy	2018-08-20	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV001787806	SCV002029247	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2021-11-11	criteria provided, single submitter	clinical testing	This sequence change in DES is predicted to replace arginine with tryptophan at codon 406, p.(Arg406Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the intermediate filament rod domain. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant is frequently de novo, and has been identified as a de novo occurrence with confirmed parental relationships in at least four individuals with a severe and early-onset cardiomyopathy with/without myopathy. All reported individuals had muscle biopsy features consistent with a desmin myopathy (PMID: 10717012, 10905661, 14991347). A knock-in mouse-model of the orthologous variant developed a phenotype consistent with desmin myopathy, including desmin-positive protein aggregate pathology in skeletal muscle tissue (PMID: 33023321). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS2_VeryStrong, PS3, PM2_Supporting, PP3.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798009	SCV002043128	pathogenic	Cardiomyopathy	2020-09-04	criteria provided, single submitter	clinical testing
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV000627795	SCV004708210	pathogenic	Desmin-related myofibrillar myopathy	2024-02-23	criteria provided, single submitter	research	Sequencing funding by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. PM2_supporting: This variant is absent from gnomAD v4 (adequate coverage >20x confirmed). PP3_moderate: REVEL score is 0.807. PM1 met: This variant occurs in exon 6 which encodes the C-terminal half of the coil 2 domain. Although disease-causing mutations spread over the entire desmin gene, they significantly cluster in exon 6. PS3_Supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product PS2_Moderate: Max 1 point awarded for 2 probands with de novo observations (paternity confirmed) and phenotype consistent with gene but not highly specific and high genetic heterogeneity. PS4 met: >=10 unrelated probands with consistent phenotype for disorder.
OMIM	RCV000627795	SCV000038599	pathogenic	Desmin-related myofibrillar myopathy	2000-06-01	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056781	SCV000087894	not provided	not provided		no assertion provided	not provided