Submissions for variant NM_004369.4(COL6A3):c.6158G>T (p.Gly2053Val)

dbSNP: rs886041329

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000334260	SCV000329750	pathogenic	not provided	2016-03-21	criteria provided, single submitter	clinical testing	The G2053V variant in the COL6A3 gene has been reported previously in the heterozygous state, in one individual with a clinical diagnosis of autosomal dominant Bethlem myopathy, characterized by hypotonia, congenital hip dysplasia, motor delays, muscle weakness, finger contractures, distal laxity, moderate respiratory insufficiency and walker-dependent ambulation (Tagliavini et al., 2014). A second, male patient, reported by Butterfield et al., (2013), harbored the heterozygous G2053V variant with an intermediate phenotype of congenital hypotonia, keloids, elevated creatinine kinase and contractures in the elbow, wrist, fingers, knee and ankle joints. The G2053V variant was not observed in approximately 6500 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 G2053V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, affecting the Glycine residue of the triple-helical region containing Gly-X-Y repeats. In silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant at the same codon (G2053C), and another in a nearby residue (G2056R), have been reported in the Human Gene Mutation Database in association with COL6A3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret G2053V as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059032	SCV001223636	pathogenic	Bethlem myopathy 1A	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2053 of the COL6A3 protein (p.Gly2053Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital muscular dystrophy (PMID: 24038877, 24907562, 34167565). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 280028). 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. This variant disrupts the triple helix domain of COL6A3. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL6A3, missense variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000334260	SCV001250157	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing