rs104886093
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000328300.11(COL4A5):c.1001G>A(p.Gly334Asp) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G334V) has been classified as Pathogenic.
Frequency
Consequence
ENST00000328300.11 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.1001G>A | p.Gly334Asp | missense_variant | 18/53 | ENST00000328300.11 | NP_203699.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1001G>A | p.Gly334Asp | missense_variant | 18/53 | 1 | NM_033380.3 | ENSP00000331902 | ||
COL4A5 | ENST00000483338.1 | c.-176G>A | 5_prime_UTR_variant | 2/20 | 1 | ENSP00000495685 | ||||
COL4A5 | ENST00000361603.7 | c.1001G>A | p.Gly334Asp | missense_variant | 18/51 | 2 | ENSP00000354505 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 28
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2022 | 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 (HGMD; Jais et al., 2000); 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: 10752524, 34758253) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2021 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine with aspartic acid at codon 334 of the COL4A5 protein (p.Gly334Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 1184578). 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 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). This variant disrupts the p.Gly334 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 19728970, 24304881), which suggests that this may be a clinically significant amino acid residue. - |
X-linked Alport syndrome Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | 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). Glycine changes in the G-X-Y repeat within the triple helix of a collagen domain are known to have a dominant-negative effect (PMID: 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Male patients tend to be more severly affected than females (PMID: 19965530). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (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 a well-established functional domain. The variant affects the glycine residue in a Gly-X-Y motif of the collagen triple helix repeat (PDB). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes at the same residue to valine and serine have previously been reported as pathogenic in individuals with X-linked Alport syndrome 1 (MIM#301050) (ClinVar, HGMD, LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. The variant has previously been classified as pathogenic in a single report (LOVD). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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
Publications
No publications associated with this variant yet.