rs864309703
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_005267.5(GJA8):c.151G>A(p.Asp51Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D51E) has been classified as Pathogenic.
Frequency
Consequence
NM_005267.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJA8 | NM_005267.5 | c.151G>A | p.Asp51Asn | missense_variant | 2/2 | ENST00000369235.2 | |
GJA8 | XM_011509417.3 | c.151G>A | p.Asp51Asn | missense_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA8 | ENST00000369235.2 | c.151G>A | p.Asp51Asn | 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:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | The variant has been previously reported as de novo in a similarly affected individual (PMID: 26694549, PS2_S) A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521485,VCV000574353, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.787, PP3_P). A missense variant is a common mechanism associated with Cataract 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 17, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp51 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 217355). This missense change has been observed in individual(s) with autosomal dominant cataract (PMID: 26694549, 29464339). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 51 of the GJA8 protein (p.Asp51Asn). - |
Uncertain significance, 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: PS4(Supporting), PM1(Supporting), PM2(Supporting), PM6(Supporting), PP3. Original variant report: PMID:26694549;29464339. Additional phenotype/s reported in these individual/s are: Microphthalmia, unilateral sclerocornea. Microphthalmia, anterior segment dysgenesis, persistent pupillary membrane. Microphthalmia, deep set eyes, corneal leukoma, buphthalmos, corectopia, nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 10, 2021 | - - |
acorea-microphthalmia-cataract syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | UOEH Ophthalmology lab, University Of Occupational And Environmental Health, Japan | Jul 07, 2023 | It provides a new screening target for prenatal diagnosis of familial acorea. - |
Developmental cataract Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Eye Genetics Research Group, Children's Medical Research Institute | Jan 09, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at