Submissions for variant NM_001927.4(DES):c.391C>A (p.Gln131Lys)

gnomAD frequency: 0.00003  dbSNP: rs771499260

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000470564	SCV000552176	uncertain significance	Desmin-related myofibrillar myopathy	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 131 of the DES protein (p.Gln131Lys). 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 411147). 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	RCV000484887	SCV000572135	uncertain significance	not provided	2016-11-11	criteria provided, single submitter	clinical testing	The Q131K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q131K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (R127P; L136P) have been reported in the Human Gene Mutation Database in association with cardiomyoapthy (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
Fulgent Genetics, Fulgent Genetics	RCV002489075	SCV002788708	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2021-07-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000484887	SCV003829056	uncertain significance	not provided	2019-12-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003168845	SCV003856704	uncertain significance	Cardiovascular phenotype	2023-02-17	criteria provided, single submitter	clinical testing	The p.Q131K variant (also known as c.391C>A), located in coding exon 1 of the DES gene, results from a C to A substitution at nucleotide position 391. The glutamine at codon 131 is replaced by lysine, an amino acid with similar properties. This variant has been detected in a hypertrophic cardiomyopathy cohort (Thomson KL et al. Genet Med, 2019 Jul;21:1576-1584). Functional studies from one group indicate this variant may not adversely impact filament formation in vitro (Brodehl A et al. Cells, 2022 Dec;11). 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.