Submissions for variant NM_003106.4(SOX2):c.389G>C (p.Gly130Ala)

dbSNP: rs121918652

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lifecell International Pvt. Ltd	RCV003227462	SCV003924051	likely pathogenic	Anophthalmia/microphthalmia-esophageal atresia syndrome		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.389G>C in Exon 1 of the SOX2 gene that results in the amino acid substitution p.Gly130Ala was identified. The observed variant has a minor allele frequency of 0.00007% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(Variant ID 12825). This variant has been previously observed in Kelberman D et al., 2006. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Neuberg Centre For Genomic Medicine, NCGM	RCV003227462	SCV004047998	uncertain significance	Anophthalmia/microphthalmia-esophageal atresia syndrome		criteria provided, single submitter	clinical testing	The missense c.389G>C (p.Gly130Ala) variant in SOX2 gene has been submitted to ClinVar as Pathogenic. It has been reported in study with individuals affected by congenital hypothalamo-pituitary disorders for mutations in the SOX2 gene along with clinical anophthalmia or microphthalmia (Kelberman et al. 2006). The variant is observed in 0.007% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Gly at position 130 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The available evidence is currently insufficient to determine the role of this variant in disease. For these reasons, this variant has been classified as Uncertain Significance.
OMIM	RCV000013673	SCV000033920	pathogenic	Optic nerve hypoplasia and abnormalities of the central nervous system	2006-09-01	no assertion criteria provided	literature only