Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Fulgent Genetics, |
RCV000673217 | SCV000893588 | likely pathogenic | Autosomal recessive Alport syndrome | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV001333199 | SCV001525715 | uncertain significance | Benign familial hematuria | 2018-09-21 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2242G>A (p.G748S) variant was previously reported as heterozygous (without second allele) in five individuals from two unrelated families with familial microhematuria with or without focal segmental glomerulosclerosis [PMID 28632965] |
Myriad Genetics, |
RCV000673217 | SCV002060392 | uncertain significance | Autosomal recessive Alport syndrome | 2021-11-03 | criteria provided, single submitter | clinical testing | NM_000092.4(COL4A4):c.2242G>A(G748S) is a missense variant classified as a variant of uncertain significance in the context of COL4A4-related Alport syndrome. G748S has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. G748S has been observed in population frequency databases (gnomAD: ASJ 0.01%). In summary, there is insufficient evidence to classify NM_000092.4(COL4A4):c.2242G>A(G748S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. |
Labcorp Genetics |
RCV001855593 | SCV002230436 | pathogenic | not provided | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 748 of the COL4A4 protein (p.Gly748Ser). This variant is present in population databases (rs762139460, gnomAD 0.01%). This missense change has been observed in individuals with COL4A4-related conditions (PMID: 28632965). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 557121). 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. |
Gene |
RCV001855593 | SCV002762423 | uncertain significance | not provided | 2022-06-10 | criteria provided, single submitter | clinical testing | 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: 31589614, 28632965, 33391746) |
Ce |
RCV001855593 | SCV003916251 | likely pathogenic | not provided | 2023-08-01 | criteria provided, single submitter | clinical testing | COL4A4: PM1:Strong, PM2, PP1, PP3, PP4 |
Fulgent Genetics, |
RCV005019154 | SCV005649121 | likely pathogenic | Autosomal recessive Alport syndrome; Hematuria, benign familial, 1 | 2024-05-14 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004737944 | SCV005360865 | pathogenic | COL4A4-related disorder | 2024-06-10 | no assertion criteria provided | clinical testing | The COL4A4 c.2242G>A variant is predicted to result in the amino acid substitution p.Gly748Ser. The Gly748Ser variant affects a Gly residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org). The majority of pathogenic variants in COL4A4 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant was reported in two individuals with focal segmental glomerulosclerosis and was shown to segregate with disease in one family (Papazachariou et al 2017. PubMed ID: 28632965). At PreventionGenetics, we have observed this variant in the heterozygous state in four individuals with COL4A4-related phenotypes and it segregated with disease in one family (Internal Data). This variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. |