2-227094271-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000092.5(COL4A4):c.1223G>A(p.Gly408Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000092.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248574Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 134952
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461464Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727018
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 408 of the COL4A4 protein (p.Gly408Glu). This variant is present in population databases (no rsID available, gnomAD 0.05%). This missense change has been observed in individuals with clinical features of Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 562349). 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 COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. The best available variant frequency is uninformative because it is below the disease allele frequency. -
Autosomal recessive Alport syndrome Pathogenic:2
Variant summary: COL4A4 c.1223G>A (p.Gly408Glu) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. This missense variant disrupts a critical glycine residue at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 4 chain, and variants affecting these glycine residues are significantly enriched in individuals with Alport syndrome (PMID: 33854215). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248574 control chromosomes. c.1223G>A has been reported at a heterozygous state in the literature in at-least one individual affected with Glomerulopathy (Groopman_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30586318). ClinVar contains an entry for this variant (Variation ID: 562349). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
The c.1223G>A variant in the COL4A4 gene is a missense variant, which results in the substitution of the highly conserved glycine residue at the 408 position to glutamic acid (p.Gly408Glu). This variant localizes to coding exon 20 of the COL4A4 gene (48 exons total; NP_000083.3) and is within the triple helical domain of the protein. To the best of our knowledge, this specific variant has not been described to be associated with disease. However, glycine substitutions within the triple helical domain of this protein are a known mechanism of disease. In silico analysis predicts this change to be deleterious and damaging to the structure and/or function of the protein (probably damaging by PolyPhen2 and damaging by SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (6/248,574), indicating it is not a common benign variant in the populations represented in this database. Of note, allele frequency is higher among individuals of Ashkenazi Jewish descent (5/10,026). Based on the evidence presented, this variant is classified as likely pathogenic. -
Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1 Pathogenic:1
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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 - Loss of function is a known mechanism of disease for this gene and is associated with COL4A4-related nephropathy. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMIDs: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (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 triple helical region (UniProt) of the collagen domain (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar and has been observed in one individual with Alport syndrome 2 in the literature (PMID: 34993602). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated in this individuals brother and nephew, however this is insufficient evidence for pathogenicity. (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 -
COL4A4-related disorder Pathogenic:1
The COL4A4 c.1223G>A variant is predicted to result in the amino acid substitution p.Gly408Glu. This variant was reported in the heterozygous state in an individual with glomerulopathy and family history of kidney disease (Table S7 of Groopman et al. 2019. PubMed ID: 30586318). At PreventionGenetics, we have observed this variant in the heterozygous state in a patient with microhematuria and proteinuria and in another patient with Alport syndrome who also carried a COL4A4 nonsense variant (internal data). The p.Gly408Glu variant affects a glycine (Gly) residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). In addition, at other glycine (Gly) residues within this domain, substitutions of a glycine (Gly) with a glutamic acid (Glu) have been widely reported to be pathogenic for autosomal recessive or dominant COL4A4 nephropathy (see for example, autosomal recessive Alport syndrome, p.Gly152Glu at Supplementary Table 1 of Morinière et al. 2014. PubMed ID: 24854265; autosomal dominant focal segmental glomerulosclerosis, p.Gly602Glu in Isaranuwatchai et al. 2023. PubMed ID: 36646731). The c.1223G>A (p.Gly408Glu) variant is reported in 0.050% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at