Submissions for variant NM_000091.5(COL4A3):c.4783G>A (p.Gly1595Arg)

gnomAD frequency: 0.00001  dbSNP: rs766208466

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761225	SCV000891181	likely pathogenic	Autosomal recessive Alport syndrome	2018-01-23	criteria provided, single submitter	clinical testing
Invitae	RCV002533862	SCV003478755	uncertain significance	not provided	2022-10-15	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 1595 of the COL4A3 protein (p.Gly1595Arg). This variant is present in population databases (rs766208466, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with COL4A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 623125). 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. 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	RCV003155307	SCV003844882	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.4783G>A (p.Gly1595Arg) results in a non-conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) 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 4.8e-05 in 249450 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (4.8e-05 vs 0.0019), allowing no conclusion about variant significance. c.4783G>A has been reported in the literature in an individual affected with segmental glomerulosclerosis (example: Shulman_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no secretary defect of this variant (Shulman_2021). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.