Submissions for variant NM_182894.3(VSX2):c.667G>A (p.Gly223Arg)

gnomAD frequency: 0.00001  dbSNP: rs755799430

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Paul Sabatier University EA-4555, Paul Sabatier University	RCV000207355	SCV000259165	pathogenic	Anophthalmia-microphthalmia syndrome	2013-01-01	criteria provided, single submitter	clinical testing	frameshit, compound heterozygosity
Illumina Laboratory Services, Illumina	RCV000778906	SCV000915314	uncertain significance	VSX2-related Microphthalmia	2017-08-03	criteria provided, single submitter	clinical testing	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.
Invitae	RCV001378265	SCV001575801	likely pathogenic	Isolated microphthalmia 2	2023-11-11	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000778906	SCV004039022	likely pathogenic	VSX2-related Microphthalmia	2023-08-10	criteria provided, single submitter	clinical testing	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.
Natera, Inc.	RCV001828043	SCV002091299	likely pathogenic	Microphthalmia	2020-09-22	no assertion criteria provided	clinical testing