Submissions for variant NM_004369.4(COL6A3):c.6212G>A (p.Gly2071Asp)

dbSNP: rs886043737

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000485229	SCV000341727	likely pathogenic	not provided	2017-03-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000485229	SCV000570859	likely pathogenic	not provided	2016-08-05	criteria provided, single submitter	clinical testing	The G2071D 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 G2071D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the Gly-X-Y motif of the triple helical domain of collagen VI, and multiple missense variants in this region of the protein 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000396169	SCV000657369	pathogenic	Bethlem myopathy 1A	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2071 of the COL6A3 protein (p.Gly2071Asp). 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: 28688748, 34167565). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 287817). 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	RCV000485229	SCV001962366	likely pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing