ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.410G>A (p.Gly137Asp)

gnomAD frequency: 0.00001  dbSNP: rs377511303
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666252 SCV000790512 uncertain significance Autosomal recessive Alport syndrome 2017-03-27 criteria provided, single submitter clinical testing
Invitae RCV001362304 SCV001558315 uncertain significance not provided 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 137 of the COL4A4 protein (p.Gly137Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with focal segmental glomerulosclerosis or steroid resistant nephrotic syndrome (PMID: 25229338, 30406062). ClinVar contains an entry for this variant (Variation ID: 551248). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282300 SCV002571779 uncertain significance not specified 2022-08-05 criteria provided, single submitter clinical testing Variant summary: COL4A4 c.410G>A (p.Gly137Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248802 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.410G>A has been reported in the literature in heterozygous individuals affected with kidney disease (Malone_2015, Varner_2018), however, these reports do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001829833 SCV002084176 uncertain significance Alport syndrome 2021-03-15 no assertion criteria provided clinical testing

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