rs672601346
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001845.6(COL4A1):c.2263G>A(p.Gly755Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G755E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001845.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A1 | NM_001845.6 | c.2263G>A | p.Gly755Arg | missense_variant | 30/52 | ENST00000375820.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A1 | ENST00000375820.10 | c.2263G>A | p.Gly755Arg | missense_variant | 30/52 | 1 | NM_001845.6 | P1 | |
COL4A1 | ENST00000649738.1 | n.2393G>A | non_coding_transcript_exon_variant | 30/31 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 25, 2023 | This missense change has been observed in individual(s) with clinical features of hereditary angiopathy with nephropathy, aneurysms and muscle cramps (PMID: 19477666, 20385946, 20733150). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 755 of the COL4A1 protein (p.Gly755Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 161974). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the triple helix domain of COL4A1. 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 COL4A1 variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 14, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2022 | Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A1 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34114234, 20733150, 20385946, 30653986, 19477666) - |
Brain small vessel disease 1 with or without ocular anomalies Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2012 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2023 | The c.2263G>A (p.G755R) alteration is located in exon 30 (coding exon 30) of the COL4A1 gene. This alteration results from a G to A substitution at nucleotide position 2263, causing the glycine (G) at amino acid position 755 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in two individuals with features consistent with COL4A1-related disorders (May, 2021; Itai, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at