ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.1118G>A (p.Gly373Glu)

gnomAD frequency: 0.00001  dbSNP: rs755649235
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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 Inc RCV000516503 SCV000612957 pathogenic not provided 2015-09-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001536127 SCV001752846 likely pathogenic Autosomal recessive Alport syndrome; Benign familial hematuria 2021-06-30 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003409732 SCV004113017 likely pathogenic COL4A4-related condition 2023-06-13 criteria provided, single submitter clinical testing The COL4A4 c.1118G>A variant is predicted to result in the amino acid substitution p.Gly373Glu. This variant was with a COL4A4 nonsense variant in an individual with Alport syndrome (Patient 26, Supplementary Table 1, Morinière et al 2014. PubMed ID: 24854265). The Gly373Glu variant affects a Gly residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org). The majority of pathogenic variants in COL4A4 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/).This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-227963496-C-T). This variant is interpreted as likely pathogenic.
Invitae RCV000516503 SCV004294004 uncertain significance not provided 2022-11-28 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 447179). This missense change has been observed in individual(s) with clinical features of autosomal recessive Alport syndrome (PMID: 24854265). This variant is present in population databases (rs755649235, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 373 of the COL4A4 protein (p.Gly373Glu). 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 COL4A4 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.
Counsyl RCV000665733 SCV000789900 likely pathogenic Autosomal recessive Alport syndrome 2017-03-22 no assertion criteria provided clinical testing

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