ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.1372G>C (p.Gly458Arg)

gnomAD frequency: 0.00002  dbSNP: rs757341933
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000517256 SCV000612941 likely pathogenic not provided 2020-02-10 criteria provided, single submitter clinical testing The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. The frequency of this variant in the general population is consistent with pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV000763078 SCV000893590 likely pathogenic Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000517256 SCV001414490 pathogenic not provided 2023-08-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly458 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been observed in individuals with COL4A3-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. ClinVar contains an entry for this variant (Variation ID: 447166). This missense change has been observed in individuals with clinical features of autosomal dominant Alport syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757341933, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 458 of the COL4A3 protein (p.Gly458Arg).
GeneDx RCV000517256 SCV003805454 uncertain significance not provided 2023-02-23 criteria provided, single submitter clinical testing Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences RCV004742476 SCV005364343 likely pathogenic COL4A3-related disorder 2024-09-25 no assertion criteria provided clinical testing The COL4A3 c.1372G>C variant is predicted to result in the amino acid substitution p.Gly458Arg. The p.Gly458Arg variant affects a Gly residue of the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). This variant has been reported in a patient tested using a panel for chronic renal disease (Bleyer et al., 2022. PubMed ID: 35325889, Table S3). At PreventionGenetics, we have observed this variant in other unrelated patients with features of COL4A3-related disorders (internal data). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.

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