ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.3643C>T (p.Arg1215Ter) (rs368434069)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760445 SCV000890329 pathogenic not provided 2021-07-15 criteria provided, single submitter clinical testing Identified as heterozygous in asymptomatic adult family members of an individual with Alport syndrome, which is consistent with an autosomal recessive mode of inheritance for this variant (Furlano et al., 2021); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33838161, 31589614, 14582039, 27535533, 26594346)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199941 SCV001370731 likely pathogenic Alport syndrome, autosomal recessive 2020-05-22 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.3643C>T (p.Arg1215X) 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 9e-06 in 221912 control chromosomes (gnomAD). c.3643C>T has been reported in the literature in at least one individual (homozygous) affected with Alport Syndrome, Autosomal Recessive (Vega_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000760445 SCV001590599 pathogenic not provided 2020-10-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1215*) 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 individual(s) with Alport syndrome (PMID: 14582039). ClinVar contains an entry for this variant (Variation ID: 620143). Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265). For these reasons, this variant has been classified as Pathogenic.

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