Submissions for variant NM_001848.3(COL6A1):c.1603G>A (p.Gly535Arg)

dbSNP: rs764556767

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000402786	SCV000818361	uncertain significance	Bethlem myopathy 1A	2022-12-24	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs764556767, gnomAD 0.0009%). 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. 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). 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. ClinVar contains an entry for this variant (Variation ID: 283692). This variant has not been reported in the literature in individuals affected with COL6A1-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 535 of the COL6A1 protein (p.Gly535Arg).
Illumina Laboratory Services, Illumina	RCV001563598	SCV001786572	uncertain significance	Collagen 6-related myopathy	2021-03-02	criteria provided, single submitter	clinical testing	The COL6A1 c.1603G>A (p.Gly535Arg) variant is a missense variant. A literature search was performed for the gene, cDNA change and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population from the Genome Aggregation Database, though this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. The p.Gly535Arg variant is a glycine substitution in the triple helix domain of collagen VI. Glycine residues within the Gly-X-Y repeats of the triple helix domain are required for the structure and stability of fibrillar collagens, and glycine substitutions in this domain are the most commonly identified mutations in the collagen VI myopathies (Shoulders et al. 2009; Butterfield et al. 2013). Based on the limited evidence, the p.Gly535Arg variant is classified as a variant of uncertain significance for collagen type VI-related disorders.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479091	SCV004223039	uncertain significance	not specified	2023-11-21	criteria provided, single submitter	clinical testing	Variant summary: COL6A1 c.1603G>A (p.Gly535Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250686 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1603G>A in individuals affected with Collagen Type VI-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease, however evidence for critical amino acid of this variant is insufficient. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; Like pathogenic, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000293620	SCV005900849	likely pathogenic	not provided	2024-09-18	criteria provided, single submitter	clinical testing	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 at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Eurofins Ntd Llc (ga)	RCV000293620	SCV000335957	likely pathogenic	not provided	2017-11-16	flagged submission	clinical testing