ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6966+4A>C (rs373940717)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726503 SCV000345095 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing
GeneDx RCV000726503 SCV000681368 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL6A3 gene. The c.6966+4 A>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 16/126720 (0.013%) alleles from individuals of Europeanbackground in large population cohorts (Lek et al., 2016). Several in silico splice prediction modelspredict that c.6966+4 A>C damages the natural splice donor site and may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000814755 SCV000955178 uncertain significance Bethlem myopathy 1 2019-12-06 criteria provided, single submitter clinical testing This sequence change falls in intron 30 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 (rs373940717, ExAC 0.009%). This variant has not been reported in the literature in individuals with COL6A3-related disease. ClinVar contains an entry for this variant (Variation ID: 290524). 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. 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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