Submissions for variant NM_001927.4(DES):c.109C>T (p.Arg37Trp)

gnomAD frequency: 0.00004  dbSNP: rs537881554

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000250161	SCV000320379	uncertain significance	Cardiovascular phenotype	2024-02-01	criteria provided, single submitter	clinical testing	The p.R37W variant (also known as c.109C>T), located in coding exon 1 of the DES gene, results from a C to T substitution at nucleotide position 109. The arginine at codon 37 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Eurofins Ntd Llc (ga)	RCV000594311	SCV000703353	uncertain significance	not provided	2016-11-18	criteria provided, single submitter	clinical testing
Invitae	RCV001217854	SCV001389711	uncertain significance	Desmin-related myofibrillar myopathy	2023-12-27	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 37 of the DES protein (p.Arg37Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of DES-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 264441). 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. 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.
GeneDx	RCV000594311	SCV001987790	uncertain significance	not provided	2019-05-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported as a variant of uncertain significance by two clinical laboratories in ClinVar but additional evidence is not available (ClinVar Variant ID# 264441; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002494794	SCV002777627	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2021-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114438	SCV003800897	uncertain significance	not specified	2023-01-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000594311	SCV003829060	uncertain significance	not provided	2022-01-25	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000594311	SCV004229574	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.