ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.1603G>A (p.Gly535Arg) (rs764556767)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000293620 SCV000335957 likely pathogenic not provided 2017-11-16 criteria provided, single submitter clinical testing
Invitae RCV000402786 SCV000818361 uncertain significance Bethlem myopathy 1 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 535 of the COL6A1 protein (p.Gly535Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs764556767, ExAC 0.002%). This variant has not been reported in the literature in individuals with COL6A1-related disease. ClinVar contains an entry for this variant (Variation ID: 283692). 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 15689448, 24038877) compared to the general population (ExAC). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV001563598 SCV001786572 uncertain significance Collagen VI-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.

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