Submissions for variant NM_004369.3(COL6A3):c.1975C>T (p.Arg659Cys) (rs146291186)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000725122	SCV000334257	uncertain significance	not provided	2018-07-24	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000319603	SCV000428852	benign	Collagen VI-related myopathy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000725122	SCV000617950	uncertain significance	not provided	2018-12-27	criteria provided, single submitter	clinical testing	The R659C variant in the COL6A3 gene has not been reported previously as a pathogenic variant,nor as a benign variant, to our knowledge. The R659C variant was not observed at any significantfrequency in approximately 6500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The R659C variant is a non-conservative amino acid substitution, which occurs within the VWFA 4domain and Nonhelical region at a position where amino acids with similar properties to Arginine aretolerated across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. We interpret R659C as a variant of uncertain significance.
Invitae	RCV001243245	SCV001416390	uncertain significance	Bethlem myopathy 1	2019-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 659 of the COL6A3 protein (p.Arg659Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs146291186, ExAC 0.04%). This variant has been observed in an individual with clinical suspicion of limb-girdle muscular dystrophy (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 282683). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.