Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
3billion | RCV001810012 | SCV002058860 | uncertain significance | Autosomal recessive Alport syndrome | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL4A4 related disorder (ClinVar ID: VCV000988149, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.985, 3CNET: 0.939, PP3_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
Invitae | RCV001880182 | SCV002233875 | pathogenic | not provided | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 918 of the COL4A4 protein (p.Gly918Arg). This variant is present in population databases (rs372606845, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 24033287; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 988149). 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. |
Sydney Genome Diagnostics, |
RCV001328134 | SCV001449258 | likely pathogenic | Alport syndrome | 2019-02-21 | no assertion criteria provided | clinical testing | This individual is heterozygous for the c.2752G>A variant in the COL4A4 gene, which results in the amino acid substitution of glycine to arginine at residue 918, p.(Gly918Arg). This variant is reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.003% (9 out of 280,892 alleles). This variant results in substitution of one of the invariant glycine residues within the triple helical domain of the alpha 4 chain of type IV collagen. This variant has been reported to segregate in 4 affected family members with autosomal dominant Alport syndrome in the literature (Fallerini et al 2014 Clin Genet 86:252-257). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all predict this variant to be a likely pathogenic variant. This variant is considered to be likely pathogenic according to the ACMG guidelines (Evidence used: PM1_strong, PM2, PP1, PP3). |