ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.7669-3C>T

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000796852 SCV000936382 uncertain significance Bethlem myopathy 1 2018-10-10 criteria provided, single submitter clinical testing This sequence change falls in intron 36 of the COL6A3 gene. It does not directly change the encoded amino acid sequence of the COL6A3 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs763071900, ExAC 0.03%). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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). A different variant affecting this nucleotide (c.7669C>G) has been observed in an individual affected with Ullrich congenital muscular dystrophy (PMID: 24271325). 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.

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