X-108614947-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_033380.3(COL4A5):c.2432G>T(p.Gly811Val) variant causes a missense change. 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.2432G>T | p.Gly811Val | missense_variant | Exon 30 of 53 | 1 | NM_033380.3 | ENSP00000331902.7 | ||
COL4A5 | ENST00000483338.1 | c.1256G>T | p.Gly419Val | missense_variant | Exon 14 of 20 | 1 | ENSP00000495685.1 | |||
COL4A5 | ENST00000361603.7 | c.2432G>T | p.Gly811Val | missense_variant | Exon 30 of 51 | 2 | ENSP00000354505.2 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in individual(s) with Alport syndrome (PMID: 8940267, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 811 of the COL4A5 protein (p.Gly811Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -
X-linked Alport syndrome Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional collagen domain in the Gly-X-Y motif (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. PMID 17396119 report c.2633C>A, p.(Gly811Arg) in a Slovenian family with Alport syndrome. It has also been reported once as pathogenic in ClinVar. (I) 0803 - This variant has limited previous evidence of pathogenicity. It has been reported in an individual with Alport syndrome (PMID: 8940267) and has been reported once as pathogenic in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at