ClinVar Miner

Submissions for variant NM_033380.3(COL4A5):c.1276G>A (p.Gly426Arg)

gnomAD frequency: 0.00001  dbSNP: rs104886111
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520914 SCV000617326 pathogenic not provided 2021-04-08 criteria provided, single submitter clinical testing Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15954103, 21505094, 30647093)
Gharavi Laboratory, Columbia University RCV000520914 SCV000809392 likely pathogenic not provided 2018-09-16 criteria provided, single submitter research
Invitae RCV000520914 SCV001591119 pathogenic not provided 2023-12-05 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 426 of the COL4A5 protein (p.Gly426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 15954103, 21505094, 30647093; Invitae). ClinVar contains an entry for this variant (Variation ID: 24393). 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 COL4A5 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000021272 SCV002017469 pathogenic X-linked Alport syndrome 2021-07-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000021272 SCV002810501 pathogenic X-linked Alport syndrome 2022-05-27 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003421929 SCV004117176 pathogenic COL4A5-related condition 2024-01-04 criteria provided, single submitter clinical testing The COL4A5 c.1276G>A variant is predicted to result in the amino acid substitution p.Gly426Arg. The p.Gly426Arg residue resides in the triple-helical domain (residues 42 – 1456; uniprot.org) of the COL4A5 protein where substitutions of the glycine (Gly) residue are usually expected to be pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported in individuals with Alport syndrome and/or focal segmental glomerulosclerosis (see for example, Nagel et al. 2005. PubMed ID: 15954103; Supp. Table 7 in Groopman et al. 2018. PubMed ID: 30586318; Yao et al. 2019. PubMed ID: 30647093). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000520914 SCV004227696 pathogenic not provided 2022-11-03 criteria provided, single submitter clinical testing PP2, PP3, PM1, PM2_supporting, PS4_moderate
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000021272 SCV001192774 pathogenic X-linked Alport syndrome 2019-09-25 no assertion criteria provided clinical testing

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