ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.868G>A (p.Gly290Arg) (rs121912939)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079833 SCV000224895 pathogenic not provided 2016-03-21 criteria provided, single submitter clinical testing
GeneDx RCV000079833 SCV000196773 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing The G290R mutation in the COL6A1 gene has been reported multiple times with COL6A1-related disorders (Lampe et al., 2005; Giusti et al., 2005; Butterfield et al., 2013; COL6A1 Leiden Open Variation Database). The G290R mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G290R mutation is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position in the predicted triple-helical region of the COL6A1 protein. A different missense mutation in the same codon (G290E) as well as multiple missense mutations in nearby residues have been reported in association with COL6A1-related disorders, supporting the functional importance of this region of the protein. In silico analysis predicts this mutation is probably damaging to the protein structure/function. We interpret G290R as a disease-causing mutation. The variant is found in COL6A1 panel(s).
Institute of Human Genetics,Cologne University RCV000173748 SCV000787788 pathogenic Bethlem myopathy 1 2018-04-25 no assertion criteria provided clinical testing
Invitae RCV000173748 SCV000657081 pathogenic Bethlem myopathy 1 2018-07-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 290 of the COL6A1 protein (p.Gly290Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (rs121912939, ExAC no frequency). This variant has been reported in many individuals affected with Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD) (PMID: 15689448, 24038877, 18825676, 28182637, 27708273). ClinVar contains an entry for this variant (Variation ID: 93894). The glycine residue affected by this missense change (p.Gly290) lies within the triple helix region. Glycine residues within the triple helix region are crucial to maintain fibrillar collagens' structure and stability (PMID: 7695699, 19344236). In the case of COL6A1, missense substitutions that affect glycine residues within the triplex helix domain have been reported in many patients affected with collagen VI myopathy (PMID: 24038877). For these reasons, this variant has been classified as Pathogenic.

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