ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4994G>A (p.Cys1665Tyr)

gnomAD frequency: 0.00003  dbSNP: rs376550779
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000514326 SCV000609552 likely pathogenic not provided 2017-03-17 criteria provided, single submitter clinical testing
Counsyl RCV000673499 SCV000798707 uncertain significance Autosomal recessive Alport syndrome 2018-03-20 criteria provided, single submitter clinical testing
Invitae RCV000514326 SCV002307030 pathogenic not provided 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1665 of the COL4A3 protein (p.Cys1665Tyr). This variant is present in population databases (rs376550779, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal recessive Alport syndrome (PMID: 24052634; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 445315). 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 with a positive predictive value of 80%. This variant disrupts the p.Cys1665 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24052634; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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