ClinVar Miner

Submissions for variant NM_001848.3(COL6A1):c.1056+1G>A (rs398123631)

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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 RCV000079739 SCV000226084 pathogenic not provided 2017-01-15 criteria provided, single submitter clinical testing
GeneDx RCV000079739 SCV000329924 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing The c.1056+1 G>A pathogenic variant in the COL6A1 gene has been previously reported in multiple patients with COL6A1-related disorders (Lamande et al., 1999; Pan et al., 2003; Lucioli et al., 2005; Baker et al., 2007; Kawahara et al., 2008). Reported individuals did not have a second identifiable COL6A1 pathogenic variant, and c.1056+1 G>A was found to be de novo in one case (Pan et al., 2003). This variant destroys the canonical splice donor site of intron 14 and functional studies demonstrate that it results in the skipping of exon 14, leading to abnormal gene splicing (Pan et al., 2003; Baker et al., 2007). It 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.
Invitae RCV000018714 SCV000656972 pathogenic Bethlem myopathy 1 2019-09-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the COL6A1 gene. It is expected to disrupt RNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This particular variant has been reported in the literature in multiple individuals affected with autosomal dominant Bethlem myopathy (PMID: 10419498, 15955946, 17886299). In one affected individual, this variant was shown to arise de novo (PMID: 12840783). It has also been reported to segregate with autosomal dominant Bethlem myopathy in an affected family (PMID: 23661642). Experimental studies have shown that this variant causes skipping of exon 14 in COL6A1 mRNA, and results in an abnormal protein product that is unable to be secreted by fibroblasts (PMID: 12840783, 10419498). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626814 SCV000747517 pathogenic Sensorimotor neuropathy 2017-01-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079739 SCV001247545 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
OMIM RCV000018714 SCV000038997 pathogenic Bethlem myopathy 1 2007-10-01 no assertion criteria provided literature only

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