ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6210+1G>A (rs398124126)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000175056 SCV000807203 pathogenic Ullrich congenital muscular dystrophy 1 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with a neuromuscular disorder: arthrogryposis, hypotonia, FTT, scoliosis, torticollis, fragile capillary syndrome.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080961 SCV000331158 pathogenic not provided 2015-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000080961 SCV000617316 pathogenic not provided 2016-08-15 criteria provided, single submitter clinical testing The c.6210+1 G>A pathogenic variant in the COL6A3 gene has been previously reported as a de novo heterozygous variant in multiple individuals with Ullrich congenital muscular dystrophy (Baker et al., 2005; Okada et al., 2007; Lampe et al., 2008). This pathogenic variant destroys the canonical splice donor site in intron 16 and functional studies have demonstrated that it results in skipping of exon 16 (Baker et al., 2005). Multiple other splice site variants have been reported in the Human Gene Mutation Database in association with COL6A3-related disorders (Stenson et al., 2014). Therefore, we interpret c.6201+1 G>A as a pathogenic variant, and its presence is consistent with a diagnosis of a COL6A3-related disorder
Invitae RCV000817699 SCV000958277 pathogenic Bethlem myopathy 1 2018-12-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 of the COL6A3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Ullrich congenital muscular dystrophy (UCMD) (PMID: 15563506). ClinVar contains an entry for this variant (Variation ID: 94956). Experimental studies have shown that this splice change results in exon 16 skipping (PMID: 15563506). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL6A3 are known to cause autosomal recessive COL6A3-related disorders (PMID: 20976770). However, splice site variants in COL6A3 have also been reported to cause autosomal dominant COL6A3-related disorders (PMID: 20976770, 15563506, 18366090). For these reasons, this variant has been classified as Pathogenic.

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