ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.1892G>T (p.Gly631Val)

dbSNP: rs1315862965
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV000755746 SCV000883272 uncertain significance Autosomal recessive Alport syndrome 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Alport syndrome, autosomal recessive, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/29946535). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
Invitae RCV001869019 SCV002150866 pathogenic not provided 2021-08-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly631 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been observed in individuals with COL4A3-related conditions (PMID: 26809805, 31925849, Invitae), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed in individual(s) with clinical features of Alport syndrome and/or kidney malformations (PMID: 26809805, 29100090). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 617934). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 631 of the COL4A3 protein (p.Gly631Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine.
PreventionGenetics, part of Exact Sciences RCV003396315 SCV004103583 pathogenic COL4A3-related condition 2023-10-12 criteria provided, single submitter clinical testing The COL4A3 c.1892G>T variant is predicted to result in the amino acid substitution p.Gly631Val. This variant has been reported in the heterozygous and compound heterozygous states in patients with COL4A3 related disorders (Weber et al. 2016. PubMed ID: 26809805; Sanna-Cherchi et al. 2017. PubMed ID: 29100090; Braunisch et al. 2018. PubMed ID: 29946535). The p.Gly631 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Mariyama et al. 1994. PubMed: 8083201; Savige et al. 2021. PubMed: 33854215; Gibson et al. 2022. PubMed: 35177655). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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