Submissions for variant NM_001848.3(COL6A1):c.1022G>T (p.Gly341Val)

dbSNP: rs121912935

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000521707	SCV000334053	pathogenic	not provided	2017-11-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000521707	SCV000617763	pathogenic	not provided	2018-08-06	criteria provided, single submitter	clinical testing	The G341V pathogenic variant in the COL6A1 gene has been previously reported in multiple unrelated individuals with Bethlem myopathy (Lampe et al., 2005; Lucioli et al., 2005; Deconinck et al., 2014; Ghaoui et al., 2015). Reported individuals did not have a second identifiable COL6A1 pathogenic variant, and G341V was found to be de novo in two cases (Deconinck et al., 2014; Ghaoui et al., 2015). The G341V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs within the Gly-X-Y motif in the triple helical (TH) domain of collagen VI, a region that is well-conserved across species. Additionally, a different missense variant at the same position (G341D) has been previously reported in a family with autosomal dominant Bethlem myopathy (Scacheri et al., 2002). Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000267474	SCV000656970	pathogenic	Bethlem myopathy 1A	2024-08-11	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 341 of the COL6A1 protein (p.Gly341Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant COL6A1-related conditions (PMID: 15689448, 15955946, 20576434, 22075033, 25535305, 26436962). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 282533). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL6A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL6A1. 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 COL6A1, variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). This variant disrupts the p.Gly341 amino acid residue in COL6A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11865138, 24038877). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004535283	SCV004120651	pathogenic	COL6A1-related disorder	2023-04-25	criteria provided, single submitter	clinical testing	The COL6A1 c.1022G>T variant is predicted to result in the amino acid substitution p.Gly341Val. This variant was reported in the heterozygous state in an an individual with Bethlem myopathy and found to segregate in two other affected family members, indicating autosomal dominant inheritance (Lucioli et al 2005. PubMed ID: 15955946). This variant has also been reported to occur de novo in a patient with limb girdle muscular dystrophy and in other patients with features of COL6A1-related disorders (See Table 3 Ghaoui R et al 2015. PubMed ID: 26436962; Deconinck N et al 2010. PubMed ID: 20576434; Table 1 Kim J et al 2011. PubMed ID: 22075033; Deconinck N et al 2014. PubMed ID: 25535305). A different substitution at this position (p.Gly341Asp) has also been reported in a family with autosomal dominant Bethlem myopathy (Scacheri PC et al 2002. PubMed ID: 11865138). This variant disrupts the triple helix domain of COL6A1 and glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (Long et al. 1993. PubMed ID: 8218237; Bella et al. 1994. PubMed ID: 7695699; Shoulders et al. 2009. PubMed ID: 19344236). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic for autosomal dominant COL6A1-related disorders.