ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.352G>A (p.Gly118Arg)

gnomAD frequency: 0.00001  dbSNP: rs1293137291
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668134 SCV000792685 uncertain significance Autosomal recessive Alport syndrome 2017-07-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844214 SCV002104170 uncertain significance not specified 2022-02-18 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.352G>A (p.Gly118Arg) 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 was absent in 249428 control chromosomes (gnomAD). c.352G>A has been reported in the literature in individuals affected with focal segmental glomerulosclerosis and hematuria (Xie_2014, Gibson_2021). 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: one classified the variant as uncertain significance and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000681838 SCV003525296 uncertain significance not provided 2022-03-29 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 118 of the COL4A3 protein (p.Gly118Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of COL4A3-related conditions (PMID: 25596306). ClinVar contains an entry for this variant (Variation ID: 552802). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A3 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Gharavi Laboratory, Columbia University RCV000681838 SCV000809315 likely pathogenic not provided 2018-09-16 no assertion criteria provided research

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