Submissions for variant NM_033380.3(COL4A5):c.1276G>A (p.Gly426Arg)

gnomAD frequency: 0.00001  dbSNP: rs104886111

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520914	SCV000617326	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing	Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed in large population cohorts (Lek et al., 2016); 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: 15954103, 21505094, 30647093)
Gharavi Laboratory, Columbia University	RCV000520914	SCV000809392	likely pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520914	SCV001591119	pathogenic	not provided	2024-11-04	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 426 of the COL4A5 protein (p.Gly426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 15954103, 21505094, 30647093; internal data). ClinVar contains an entry for this variant (Variation ID: 24393). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A5 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000021272	SCV002017469	pathogenic	X-linked Alport syndrome	2021-07-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000021272	SCV002810501	pathogenic	X-linked Alport syndrome	2024-01-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000520914	SCV004227696	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing	PP2, PP3, PM1, PM2_supporting, PS4_moderate
Ambry Genetics	RCV004018651	SCV004929705	likely pathogenic	Inborn genetic diseases	2023-12-28	criteria provided, single submitter	clinical testing	The c.1276G>A (p.G426R) alteration is located in exon 20 (coding exon 20) of the COL4A5 gene. This alteration results from a G to A substitution at nucleotide position 1276, causing the glycine (G) at amino acid position 426 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple individuals with clinical features of COL4A5-related Alport syndrome (Zhou, 2023; Shulman, 2021; Groopman, 2019; Yao, 2019; Ma, 2011; Nagel, 2005). This amino acid position is highly conserved in available vertebrate species. In an assay testing COL4A5 function, this variant showed a functionally abnormal result (Omachi, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000021272	SCV005375249	pathogenic	X-linked Alport syndrome	2024-10-13	criteria provided, single submitter	clinical testing	This variant (GRCh38; NM_033380.3:c.1276G>A:p.Gly426Arg) results in a missense mutation with the conversion of Glycine (Polar amino acid) to Arginine (Basic amino acid) in the COL4A5 protein. Located in a mutational hot spot and/or critical and well established functional domain without benign variation. Not observed at significant frequency in large population cohorts (gnomAD). This variant has a strong Conservation score. Multiple lines of computational evidence support a deleterious effect on the gene or gene product for this variant. ClinVar contains an entry for this variant (Variation ID: 24393). This variant is associated with the following publications: PubMed: 21505094, 15954103, 23720012, 29526710, 30586318, 27627812 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000021272	SCV005886352	pathogenic	X-linked Alport syndrome	2025-02-05	criteria provided, single submitter	clinical testing	Variant summary: COL4A5 c.1276G>A (p.Gly426Arg) results in a non-conservative amino acid change located in the Triple-helical region of the encoded protein sequence. This missense variant disrupts a critical glycine residue at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 5 chain, and variants affecting these glycine residues are significantly enriched in individuals with Alport syndrome (PMID: 33854215). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183146 control chromosomes. c.1276G>A has been reported in the heterozygous or hemizygous state in the literature in multiple individuals affected with X-Linked Alport Syndrome (example, Ma_2011, Zhou_2023, Nagel_2005, Labcorp Genetics (formerly Invitae)). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21505094, 37097554, 15954103). ClinVar contains an entry for this variant (Variation ID: 24393). Based on the evidence outlined above, the variant was classified as pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000021272	SCV001192774	pathogenic	X-linked Alport syndrome	2019-09-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421929	SCV004117176	pathogenic	COL4A5-related disorder	2024-01-04	no assertion criteria provided	clinical testing	The COL4A5 c.1276G>A variant is predicted to result in the amino acid substitution p.Gly426Arg. The p.Gly426Arg residue resides in the triple-helical domain (residues 42 – 1456; uniprot.org) of the COL4A5 protein where substitutions of the glycine (Gly) residue are usually expected to be pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported in individuals with Alport syndrome and/or focal segmental glomerulosclerosis (see for example, Nagel et al. 2005. PubMed ID: 15954103; Supp. Table 7 in Groopman et al. 2018. PubMed ID: 30586318; Yao et al. 2019. PubMed ID: 30647093). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.