rs104886111
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_033380.3(COL4A5):c.1276G>A(p.Gly426Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,208,783 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.1276G>A | p.Gly426Arg | missense_variant | 20/53 | ENST00000328300.11 | NP_203699.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1276G>A | p.Gly426Arg | missense_variant | 20/53 | 1 | NM_033380.3 | ENSP00000331902.7 | ||
COL4A5 | ENST00000483338.1 | c.100G>A | p.Gly34Arg | missense_variant | 4/20 | 1 | ENSP00000495685.1 | |||
COL4A5 | ENST00000361603.7 | c.1276G>A | p.Gly426Arg | missense_variant | 20/51 | 2 | ENSP00000354505.2 |
Frequencies
GnomAD3 genomes AF: 0.00000889 AC: 1AN: 112532Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34710
GnomAD4 exome AF: 0.00000274 AC: 3AN: 1096251Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1AN XY: 362499
GnomAD4 genome AF: 0.00000889 AC: 1AN: 112532Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34710
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 03, 2022 | PP2, PP3, PM1, PM2_supporting, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2021 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 05, 2023 | 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; Invitae). ClinVar contains an entry for this variant (Variation ID: 24393). 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 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. - |
X-linked Alport syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 06, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Sep 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Oct 13, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 23, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2023 | 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. - |
COL4A5-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at