Submissions for variant NM_001927.4(DES):c.1049G>A (p.Arg350Gln)

gnomAD frequency: 0.00002  dbSNP: rs57965306

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000732254	SCV000860179	uncertain significance	not provided	2018-03-16	criteria provided, single submitter	clinical testing
Invitae	RCV001067513	SCV001232579	uncertain significance	Desmin-related myofibrillar myopathy	2023-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 350 of the DES protein (p.Arg350Gln). This variant is present in population databases (rs57965306, gnomAD 0.005%). This missense change has been observed in individual(s) with centronuclear myopathy and/or suffered a sudden unexplained death (PMID: 29382405, 29915097). ClinVar contains an entry for this variant (Variation ID: 596421). 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. 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. 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	RCV002388369	SCV002703159	uncertain significance	Cardiovascular phenotype	2021-09-16	criteria provided, single submitter	clinical testing	The p.R350Q variant (also known as c.1049G>A), located in coding exon 6 of the DES gene, results from a G to A substitution at nucleotide position 1049. The arginine at codon 350 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a sudden unexplained death cohort in an individual with an additional alteration in a different cardiac-related gene (Shanks GW et al. Circulation, 2018 06;137:2705-2715). Additionally, this alteration has been reported in an individual with proximal muscle weakness and centronuclear myopathy identified on biopsy (Wu L et al. Can J Neurol Sci, 2018 05;45:262-268). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV002477711	SCV002777448	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2021-08-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000732254	SCV003829024	uncertain significance	not provided	2019-07-08	criteria provided, single submitter	clinical testing