Submissions for variant NM_001848.3(COL6A1):c.877G>A (p.Gly293Arg)

dbSNP: rs398123643

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173743	SCV000224891	likely pathogenic	not provided	2015-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000173744	SCV000657083	pathogenic	Bethlem myopathy 1A	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 293 of the COL6A1 protein (p.Gly293Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Bethlem myopathy and Ullrich congenital muscular dystrophy (PMID: 20976770, 22075033, 22975586, 24038877, 24223098, 26867126, 27363342, 27854213). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 93895). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL6A1 protein function with a positive predictive value of 80%. 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). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000173743	SCV001501809	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000173743	SCV001983813	pathogenic	not provided	2022-09-21	criteria provided, single submitter	clinical testing	Reported to segregate with disease in affected individuals from two unrelated families in published literature (Kim et al., 2012; Cruz et al., 2016); Replaces the glycine in the canonical Gly-X-Y repeat of the triple helical domain and is expected to disrupt normal protein folding and function, which is an established mechanism of disease (HGMD); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31561939, 27854213, 28688748, 28831785, 27363342, 30808312, 32065942, 20976770, 26867126, 22975586, 19344236, 15689448, 24223098, 33146414, 31069529, 33441455, 24038877, 34167565, 25473036, 27159402, 33726816, 29419890, 22075033, 35457228)
Revvity Omics, Revvity	RCV000173743	SCV002023323	likely pathogenic	not provided	2021-02-16	criteria provided, single submitter	clinical testing
DASA	RCV001813755	SCV002061156	pathogenic	Collagen 6-related myopathy	2022-01-05	criteria provided, single submitter	clinical testing	The c.877G>A;p.(Gly293Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 93895; PMID: 27854213; 26867126; 24223098; 24038877; 22975586; 22075033) - PS4. Same amino acid change as a previously established pathogenic variant regardless of nucleotide change(Clinvar ID: 1076562) - PS1. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Collagen; PMID: 24038877) - PM1. This variant is not present in population databases (rs398123643, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 944129; 639559) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 22975586) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion	RCV000173744	SCV002521493	pathogenic	Bethlem myopathy 1A	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093895). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 20976770, 22075033, 22975586, 24038877, 24223098, 26867126, 27363342, 27854213). Different missense changes at the same codon (p.Gly293Glu, p.Gly293Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000639559, VCV000944129). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002483138	SCV002794513	pathogenic	Bethlem myopathy 1A; Ullrich congenital muscular dystrophy 1A	2022-01-21	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000173744	SCV005068192	pathogenic	Bethlem myopathy 1A		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000173743	SCV001808160	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000173743	SCV001923933	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000173743	SCV001951310	pathogenic	not provided		no assertion criteria provided	clinical testing