rs281874674
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_033380.3(COL4A5):c.1690G>C(p.Gly564Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G564C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_033380.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.1690G>C | p.Gly564Arg | missense_variant | 24/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1690G>C | p.Gly564Arg | missense_variant | 24/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000483338.1 | c.514G>C | p.Gly172Arg | missense_variant | 8/20 | 1 | |||
COL4A5 | ENST00000361603.7 | c.1690G>C | p.Gly564Arg | missense_variant | 24/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2022 | 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. This variant disrupts the p.Gly564 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19965530, 32939031; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 242342). This missense change has been observed in individual(s) with X-linked Alport syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 564 of the COL4A5 protein (p.Gly564Arg). - |
X-linked Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Dhiti Omics Technologies Pvt. Ltd. | Jun 04, 2015 | The clinical significance was assigned and evaluated based on the ACMG guidelines for Variant Classification (Richards et al, 2015). This variant is absent in population databases (PM2); is a novel missense change at an amino acid residue where a different pathogenic missense change has been seen before (PM5) (Tan et al, 2010, PMC2801648); the patient's phenotype was highly specific for this gene (PP4) and multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3). It is an X-linked dominant inheritance where the mother and daughter of the proband are carriers for the same variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at