ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.3044G>A (p.Gly1015Glu)

gnomAD frequency: 0.00008  dbSNP: rs764323652
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673247 SCV000798428 uncertain significance Autosomal recessive Alport syndrome 2018-03-05 criteria provided, single submitter clinical testing
Medical Genetics, University of Parma RCV001089914 SCV001245147 likely pathogenic Autosomal dominant Alport syndrome; Benign familial hematuria 2020-03-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001868269 SCV002212056 pathogenic not provided 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1015 of the COL4A4 protein (p.Gly1015Glu). This variant is present in population databases (rs764323652, gnomAD 0.01%). This missense change has been observed in individuals with Alport syndrome (PMID: 28632965, 33369211; Invitae). ClinVar contains an entry for this variant (Variation ID: 557146). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV002468598 SCV002765001 likely pathogenic Benign familial hematuria 2022-03-07 criteria provided, single submitter clinical testing
GeneDx RCV001868269 SCV004012403 uncertain significance not provided 2024-04-01 criteria provided, single submitter clinical testing Reported in individuals with microscopic hematuria with or without associated ocular abnormalities in published literature; clinical information is limited (PMID: 35419377, 28632965, 33369211); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 gene; This variant is associated with the following publications: (PMID: 34426522, 35419377, 33369211, 28632965)
PreventionGenetics, part of Exact Sciences RCV004737945 SCV005362369 pathogenic COL4A4-related disorder 2024-06-06 no assertion criteria provided clinical testing The COL4A4 c.3044G>A variant is predicted to result in the amino acid substitution p.Gly1015Glu. This variant affects a glycine (Gly) residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported in individuals with familial microscopic hematuria (Family GR-5416 in Papazachariou et al. 2017. PubMed ID: 28632965; Supp. Table 1 in Uliana et al. 2021. PubMed ID: 33369211; Cerkauskaite et al. 2022. PubMed ID: 35419377). This variant is reported in 0.011% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic for COL4A4-related renal disorders.

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