rs755799430
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1PM1PM2PM5PP3_StrongPP5
The NM_182894.3(VSX2):c.667G>A(p.Gly223Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,000 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G223A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_182894.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VSX2 | NM_182894.3 | c.667G>A | p.Gly223Arg | missense_variant | 4/5 | ENST00000261980.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VSX2 | ENST00000261980.3 | c.667G>A | p.Gly223Arg | missense_variant | 4/5 | 1 | NM_182894.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251320Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135798
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727216
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
VSX2-related Microphthalmia Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2023 | Variant summary: VSX2 c.667G>A (p.Gly223Arg) 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 8e-06 in 251320 control chromosomes (gnomAD). c.667G>A has been reported in the literature as a biallelic genotype in at least two individuals affected with VSX2-related Microphthalmia, including one case where it was confrmed to be in trans with a pathogenic variant and the proband also had an affected sibling (who was not genetically tested) (e.g. Chassaing_2014, Matias-Perez_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same amino acid (c.668G>C, p.Gly223Ala) has been reported in association with affected individuals in the HGMD database, suggesting Gly223 is likely important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 24033328, 30181649). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 03, 2017 | The VSX2 c.667G>A (p.Gly223Arg) missense variant has been reported in one study in which it is found in a compound heterozygous state with a frameshift variant on the second allele in one individual with bilateral microphthalmia, cataracts and colobomas (Chassaing et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.000096 in the African population of the Exome Aggregation Consortium. This is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, the p.Gly223Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for VSX2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Microphthalmia Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 22, 2020 | - - |
Isolated microphthalmia 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 223 of the VSX2 protein (p.Gly223Arg). This variant is present in population databases (rs755799430, gnomAD 0.007%). This missense change has been observed in individual(s) with VSX2-related conditions (PMID: 24033328, 30181649). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 221963). 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 with a positive predictive value of 80%. This variant disrupts the p.Gly223 amino acid residue in VSX2. Other variant(s) that disrupt this residue have been observed in individuals with VSX2-related conditions (PMID: 21976963), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Anophthalmia-microphthalmia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Paul Sabatier University EA-4555, Paul Sabatier University | Jan 01, 2013 | frameshit, compound heterozygosity - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at