ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.1145G>C (p.Gly382Ala)

gnomAD frequency: 0.00001  dbSNP: rs751952236
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001588282 SCV001826714 pathogenic not provided 2022-08-01 criteria provided, single submitter clinical testing Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Jais et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 29204651, 24077912, 10752524, 34400539)
Fulgent Genetics, Fulgent Genetics RCV002495959 SCV002802061 pathogenic Autosomal recessive Alport syndrome; Benign familial hematuria 2022-03-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001588282 SCV003453968 uncertain significance not provided 2022-10-13 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 382 of the COL4A4 protein (p.Gly382Ala). This variant is present in population databases (rs751952236, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Alport syndrome (PMID: 29204651; Invitae). ClinVar contains an entry for this variant (Variation ID: 1219193). 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. This variant disrupts the p.Gly382 amino acid residue in COL4A4. Other variant(s) that disrupt this residue have been observed in individuals with COL4A4-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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.

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