Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
RCV001199941 | SCV001370731 | pathogenic | Autosomal recessive Alport syndrome | 2022-09-30 | 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 9e-06 in 221912 control chromosomes. c.3643C>T has been reported in the literature in both homozygous and compound heterozygous individuals affected with Alport Syndrome, Autosomal Recessive (Vega_2003, Zhang_2021), as well as unaffected heterozygous carriers related to an affected patient (Furlano_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV000760445 | SCV001590599 | pathogenic | not provided | 2022-01-11 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 620143). This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 14582039). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). |