ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6890G>C (p.Gly2297Ala) (rs886043576)

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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 RCV000710911 SCV000340817 likely pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710911 SCV000841221 likely pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing
Invitae RCV001207298 SCV001378643 uncertain significance Bethlem myopathy 1 2019-09-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 2297 of the COL6A3 protein (p.Gly2297Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the heterozygous state in individuals affected with progressive limb-girdle muscular dystrophy; however, these individuals were also found to have a homozygous pathogenic variant in another gene (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 287133). 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. 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 disease (PMID: 15689448, 24038877) compared to the general population (ExAC). 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.

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