ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.3210+1G>A (rs1553762314)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670389 SCV000795234 likely pathogenic Alport syndrome, autosomal recessive 2017-11-07 criteria provided, single submitter clinical testing
Invitae RCV001213668 SCV001385313 likely pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 37 of the COL4A3 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 an individual affected with autosomal recessive Alport syndrome (PMID: 24052634). ClinVar contains an entry for this variant (Variation ID: 554710). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, 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 COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670389 SCV001623348 likely pathogenic Alport syndrome, autosomal recessive 2021-04-19 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.3210+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict that the variant abolishes a 5-prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244902 control chromosomes. c.3210+1G>A has been reported in the literature in at least one individual affected with Alport Syndrome, Autosomal Recessive (e.g. Storey_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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