ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.2768_2778del (p.Val923fs) (rs766306957)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666969 SCV000791349 pathogenic Alport syndrome, autosomal recessive 2017-05-08 criteria provided, single submitter clinical testing
Eurofins NTD, LLC RCV000729022 SCV000856655 pathogenic not provided 2017-09-20 criteria provided, single submitter clinical testing
Invitae RCV000729022 SCV001207327 pathogenic not provided 2020-10-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val923Glufs*13) 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 to be homozygous or in combination with another COL4A3 variant in individual(s) with Alport syndrome (PMID: 24052634, 24854265). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551819). 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 RCV000666969 SCV001361059 pathogenic Alport syndrome, autosomal recessive 2019-02-04 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.2768_2778del11 (p.Val923GlufsX13) 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 2.4e-05 in 246024 control chromosomes (gnomAD). c.2768_2778del11 has been reported in the literature in homozygous and compound heterozygous individuals affected with Alport Syndrome, autosomal recessive (Storey 2013, Moriniere 2014). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000729022 SCV001758474 pathogenic not provided 2019-12-27 criteria provided, single submitter clinical testing Frameshift 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: 30665703, 24052634, 24854265)
Natera, Inc. RCV001273240 SCV001456035 pathogenic Alport syndrome 2020-09-16 no assertion criteria provided clinical testing

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