ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6354+1G>A (rs886042883)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622451 SCV000742627 likely pathogenic Inborn genetic diseases 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000578834 SCV000338903 pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing
GeneDx RCV000578834 SCV000681255 pathogenic not provided 2017-12-12 criteria provided, single submitter clinical testing The c.6354+1G>A variant in the COL6A3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 19. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.6354+1G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.6354+1G>A as a pathogenic variant.
Invitae RCV000319175 SCV000657374 pathogenic Bethlem myopathy 1 2018-07-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 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 in individuals affected with Bethlem myopathy (PMID: 28688748, Invitae). ClinVar contains an entry for this variant (Variation ID: 285748). 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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