rs864309688
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005267.5(GJA8):āc.134G>Cā(p.Trp45Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (ā ā ). 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>C | p.Trp45Ser | missense_variant | 2/2 | ENST00000369235.2 | |
GJA8 | XM_011509417.3 | c.134G>C | p.Trp45Ser | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA8 | ENST00000369235.2 | c.134G>C | p.Trp45Ser | missense_variant | 2/2 | NM_005267.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Cataract 1 multiple types Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GJA8-related disorder (ClinVar ID: VCV000217335 / PMID: 18334946). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26694549). Different missense changes at the same codon (p.Trp45Arg, p.Trp45Leu) have been reported to be associated with GJA8-related disorder (ClinVar ID: VCV000845873 / PMID: 28392901 , 30498267). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA8 function (PMID: 21228318, 25003127). 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. ClinVar contains an entry for this variant (Variation ID: 217335). This missense change has been observed in individual(s) with bilateral congenital cataracts (PMID: 18334946, 26694549). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 45 of the GJA8 protein (p.Trp45Ser). - |
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(Moderate), PM1(Supporting), PS4(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:18334946;26694549;28839118;30076350. The cataract phenotype/s reported for this variant are: Jellyfish-like, and Anterior cortical/nuclear. Additional phenotype/s reported in these individual/s are: latent nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 - |
Developmental cataract Pathogenic:2
Pathogenic, no assertion criteria provided | research | Eye Genetics Research Group, Children's Medical Research Institute | Jan 09, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Ophthalmology, Flinders University | Jul 29, 2016 | - - |
GJA8-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 12, 2024 | The GJA8 c.134G>C variant is predicted to result in the amino acid substitution p.Trp45Ser. This variant has been reported to segregate with disease in a kindred with congenital cataracts and microcornea (Vanita et al. 2008. PubMed ID: 18334946). This variant has been reported in additional, unrelated individuals with congenital cataracts (Javadiyan et al. 2017. PubMed ID: 28839118; Ma et al. 2016. PubMed ID: 26694549; Zamani et al. 2022. PubMed ID: 35754085). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at