ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.2732C>G (p.Pro911Arg)

gnomAD frequency: 0.00002  dbSNP: rs764465049
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV002225149 SCV002503620 uncertain significance Autosomal recessive Alport syndrome 2023-03-30 criteria provided, single submitter clinical testing This sequence change is predicted to replace proline with arginine at codon 911 of the COL4A4 protein, p.(Pro911Arg). The proline residue is moderately conserved (100 vertebrates, UCSC), and is located at the Y position in the G-X-Y collagen triple helix repeat in one of the intermediate collagenous domains. There is a large physicochemical difference between proline and arginine. The variant is present in a large population cohort at a frequency of 0.002%, consistent with recessive disease (rs764465049, 5/249,194 alleles, 0 homozygotes in gnomAD v2.1.1). It has not been previously reported in the relevant medical literature or databases. The variant has been identified in a suspected Alport syndrome case with a likely pathogenic COL4A4 variant (p.Ile29_Leu30del; Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2, PM3_Supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV003089195 SCV003470518 likely benign not provided 2023-12-18 criteria provided, single submitter clinical testing

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