ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.3683G>T (p.Gly1228Val)

gnomAD frequency: 0.00001  dbSNP: rs1183958961
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV001535999 SCV001752674 likely pathogenic Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria 2021-06-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002568227 SCV003222279 likely pathogenic not provided 2024-02-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1228 of the COL4A3 protein (p.Gly1228Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of autosomal dominant COL4A3-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1179129). 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 COL4A3 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV003346606 SCV004076511 likely pathogenic Inborn genetic diseases 2023-08-16 criteria provided, single submitter clinical testing The c.3683G>T (p.G1228V) alteration is located in exon 42 (coding exon 42) of the COL4A3 gene. This alteration results from a G to T substitution at nucleotide position 3683, causing the glycine (G) at amino acid position 1228 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/186352) total alleles studied. The highest observed frequency was 0.007% (1/13976) of East Asian alleles. This amino acid position is highly conserved in available vertebrate species. The p.G1228 amino acid is located within the triple-helical domain of the collagen alpha-3(IV) chain, and this alteration affects one of the highly conserved glycine residues in the Gly-X-Y motif that make up this domain (Ramshaw, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

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