Submissions for variant NM_001927.4(DES):c.1243C>T (p.Arg415Trp)

gnomAD frequency: 0.00004  dbSNP: rs751942358

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656841	SCV000235792	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	Reported in association with skeletal myopathy and muscle weakness (Goldfarb et al., 2008; Bugiardini et al., 2018; Khorasanizadeh et al., 2019); 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: 19587455, 23143191, 16401858, 29997562, 19181099, Khorasanizadeh_article_2019)
Eurofins Ntd Llc (ga)	RCV000656841	SCV000335190	uncertain significance	not provided	2017-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000532526	SCV000654166	uncertain significance	Desmin-related myofibrillar myopathy	2024-01-19	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 415 of the DES protein (p.Arg415Trp). This variant is present in population databases (rs751942358, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of DES-related conditions (PMID: 19181099). ClinVar contains an entry for this variant (Variation ID: 201709). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics	RCV002381604	SCV002671299	uncertain significance	Cardiovascular phenotype	2023-02-28	criteria provided, single submitter	clinical testing	The p.R415W variant (also known as c.1243C>T), located in coding exon 6 of the DES gene, results from a C to T substitution at nucleotide position 1243. The arginine at codon 415 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in myopathy cohorts; however, clinical details were limited and an additional alteration in a cardiac-related gene was identified in one case (Goldfarb LG et al. Adv Exp Med Biol, 2008;642:131-64; Bugiardini E et al. Front Neurol, 2018 Jun;9:456). 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.
Fulgent Genetics, Fulgent Genetics	RCV002492826	SCV002792601	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2021-09-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656841	SCV003829009	uncertain significance	not provided	2021-01-08	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV002265670	SCV002074835	not provided	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-03-2017 by Lab or GTR ID 500031. This participant was tested at multiple clinical laboratories and the variant was classified as uncertain at both laboratories. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.