ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4337_4338del (p.Phe1446fs) (rs776244020)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001061939 SCV001226704 pathogenic not provided 2020-06-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1446Cysfs*63) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs776244020, ExAC 0.02%). This variant has not been reported in the literature in individuals with COL4A3-related conditions. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001532939 SCV001748751 likely pathogenic Alport syndrome, autosomal recessive 2021-06-28 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.4337_4338delTT (p.Phe1446CysfsX63) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 249536 control chromosomes. To our knowledge, no occurrence of c.4337_4338delTT in individuals affected with Alport Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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