chr1-147908089-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005267.5(GJA8):c.134G>T(p.Trp45Leu) 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. 12/21 in silico tools predict a damaging 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. W45R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005267.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJA8 | NM_005267.5 | c.134G>T | p.Trp45Leu | missense_variant | 2/2 | ENST00000369235.2 | |
GJA8 | XM_011509417.3 | c.134G>T | p.Trp45Leu | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA8 | ENST00000369235.2 | c.134G>T | p.Trp45Leu | missense_variant | 2/2 | NM_005267.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cataract 1 multiple types Pathogenic:3
Likely pathogenic, criteria provided, single submitter | curation | Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania | Jan 21, 2023 | Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Supporting), PM1(Supporting), PM2(Supporting), PP3. Original variant report: PMID:28392901;29464339;32830442;33494148;35980487. Additional phenotype/s reported in these individual/s are: Microphthalmia and nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with cataract 1, multiple types (MIM#116200). While loss of function has been described for missense variants in this gene (OMIM), dominant negative is a likely mechansim because this protein forms multimers (PMID: 33218330) and variants resulting in protein truncation are prevalent in the general population (gnomAD). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Pathogenic missense variants are clustered within the connexin domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and observed in two unrelated families with cataracts. Additionally, it has been observed de novo in another individual with cataracts (ClinVar, PMID: 33494148, PMID: 29464339, PMID: 28392901). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has segregated within a large family with cataracts, microphthalmia and nystagmus (PMID: 29464339). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 28392901, 29464339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 845873). 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 GJA8 protein function. This variant disrupts the p.Trp45 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18334946, 21228318, 25003127, 26694549). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 45 of the GJA8 protein (p.Trp45Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at