ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.850G>A (p.Gly284Arg) (rs121912938)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000079828 SCV000613009 pathogenic not provided 2017-06-09 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000079828 SCV000611013 pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079828 SCV000233043 pathogenic not provided 2016-07-20 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology,Institute of Human Genetics RCV000180574 SCV000747831 uncertain significance Ullrich congenital muscular dystrophy 1 2017-02-28 no assertion criteria provided clinical testing The observed variant c.850G>A (p.Gly284Arg) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, tolerated by SIFT, and probably damaging by PolyPhen2.
GeneDx RCV000079828 SCV000196771 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing The G284R mutation in the COL6A1 gene has been reported previously in the heterozygous state in two unrelated individuals with Ullrich muscular dystrophy (Lampe et al., 2005). The G284R 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 G284R 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 occurs within the Gly-X-Y motif in the triple helical (TH) domain of collagen VI, a region that is well-conserved across species. In a study of individuals with collagen VI myopathies due to Glycine substitutions in the TH domain, mutations were found to be dominantly acting in 96% (186/194) of cases (Butterfield et al., 2013). In silico analysis predicts this mutation is probably damaging to the protein structure/function. Additionally, missense mutations in nearby residues (G281R; G281E; G281A; G287R; G290R; G290E) have been reported in association with COL6A1-related disorders, supporting the functional importance of this region of the protein. We interpret G284R as a disease-causing mutation associated with Ullrich congenital muscular dystrophy. The variant is found in COL6A1 panel(s).
Invitae RCV000180573 SCV000657080 pathogenic Bethlem myopathy 1 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 284 of the COL6A1 protein (p.Gly284Arg). 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 (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Ullrich congenital muscular dystrophy (UCMD) (PMID: 24038877, 24801232). Additional individuals have been reported with phenotypes including early severe UCMD, intermediate severity UCMD, and mild Bethlem myopathy (PMID: 15689448, 24038877, 18825676, 16130093, 19564581). ClinVar contains an entry for this variant (Variation ID: 17180). 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 individuals affected with collagen VI myopathy (PMID: 24038877) Experimental studies have shown that fibroblasts containing this missense change have reduced cellular adhesion when compared to fibroblasts containing wild type collagen VI protein (PMID: 17785674). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018720 SCV000039003 pathogenic Ullrich congenital muscular dystrophy 1, autosomal dominant 2009-07-07 no assertion criteria provided literature only

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