ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.1043C>T (p.Ser348Leu) (rs142882745)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725393 SCV000336593 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000267314 SCV000436502 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 RCV000725393 SCV000568057 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing The S348L variant in the COL6A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports S348L was observed in 13/8,600 (0.15%) alleles from individuals of European background, indicating it may be a rare variant in this population. The S348L variant 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 at a position that is conserved in mammals, and in silico analysis predicts this variant is likely damaging to the protein structure/function. We interpret S348L as a variant of uncertain significance.
Athena Diagnostics Inc RCV000323225 SCV000613006 uncertain significance not specified 2017-04-14 criteria provided, single submitter clinical testing
Invitae RCV000653553 SCV000775434 uncertain significance Bethlem myopathy 1 2019-12-21 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 348 of the COL6A1 protein (p.Ser348Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs142882745, ExAC 0.1%). This variant has been observed in the heterozygous state in several individuals with clinical suspicion of limb-girdle muscular dystrophy (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 284109). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725393 SCV001153577 uncertain significance not provided 2017-10-01 criteria provided, single submitter clinical testing

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