ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4347_4353del (p.Arg1450fs) (rs748026887)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665013 SCV000789066 pathogenic Alport syndrome, autosomal recessive 2016-12-28 criteria provided, single submitter clinical testing
Invitae RCV001061072 SCV001225801 pathogenic not provided 2020-03-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1450Valfs*77) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with Alport syndrome (PMID: 7780062, 24052634). ClinVar contains an entry for this variant (Variation ID: 550302). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665013 SCV001361319 pathogenic Alport syndrome, autosomal recessive 2019-11-05 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.4347_4353delCCGACAC (p.Arg1450ValfsX77) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 249534 control chromosomes. c.4347_4353delCCGACAC has been reported in the literature in individuals affected with autosomal recessive Alport Syndrome (Ding_1995, Storey_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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