ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.2621_2622delinsT (p.Gly874fs) (rs1553760257)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667128 SCV000791529 pathogenic Alport syndrome, autosomal recessive 2017-05-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667128 SCV000917261 pathogenic Alport syndrome, autosomal recessive 2021-04-21 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.2621_2622delinsT (p.Gly874ValfsX9) 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 3.6e-05 in 280726 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (3.6e-05 vs 0.0019), allowing no conclusion about variant significance. c.2621_2622delinsT has been reported in the literature in multiple individuals affected with Alport Syndrome, Autosomal Recessive, including one homozygous patient (Heidet_2001, Storey_2013, Moriniere_2014, Papazachariou_2014, Bierzynska_2017). 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 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000823486 SCV000964347 pathogenic not provided 2019-11-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly874Valfs*9) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs759043857, ExAC 0.005%). This variant has been observed to be homozygous or in combination with another COL4A3 variant in individuals affected with Alport syndrome (PMID: 11134255, 24052634, 24854265, 25514610), and has been reported on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (PMID: 28117080). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as 2621delGAinsT in the literature. ClinVar contains an entry for this variant (Variation ID: 551951). 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.
PerkinElmer Genomics RCV000823486 SCV002017458 pathogenic not provided 2021-06-11 no assertion criteria provided clinical testing

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