rs121912545
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The ENST00000261980.3(VSX2):c.679C>T(p.Arg227Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,808 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000261980.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VSX2 | NM_182894.3 | c.679C>T | p.Arg227Trp | missense_variant | 4/5 | ENST00000261980.3 | NP_878314.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VSX2 | ENST00000261980.3 | c.679C>T | p.Arg227Trp | missense_variant | 4/5 | 1 | NM_182894.3 | ENSP00000261980 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251100Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135674
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461636Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727094
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Isolated microphthalmia 2 Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2004 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VSX2 function (PMID: 23028343). 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 VSX2 protein function. ClinVar contains an entry for this variant (Variation ID: 14862). This missense change has been observed in individuals with microphthalmia (PMID: 15257456, 20414678). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912545, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 227 of the VSX2 protein (p.Arg227Trp). - |
Anophthalmia;C0026010:Microphthalmia Pathogenic:1
Pathogenic, no assertion criteria provided | research | Molecular Genetics Laboratory, Institute for Ophthalmic Research | Dec 13, 2017 | - - |
VSX2-related Microphthalmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2024 | Variant summary: VSX2 c.679C>T (p.Arg227Trp) results in a non-conservative amino acid change located in the CVC domain (IPR023339) of the encoded protein sequence. 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 1.6e-05 in 251100 control chromosomes (gnomAD). c.679C>T has been reported in the literature in several homozygous individuals affected with VSX2-related Microphthalmia (Bar-Yosef_2004). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 15257456). ClinVar contains an entry for this variant (Variation ID: 14862). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Microphthalmia, isolated, with coloboma 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at