Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001042635 | SCV001206331 | uncertain significance | Holoprosencephaly 9; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome | 2019-03-06 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GLI2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 575 of the GLI2 protein (p.Tyr575His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193461 | SCV001362309 | uncertain significance | not specified | 2019-12-11 | criteria provided, single submitter | clinical testing | Variant summary: GLI2 c.1723T>C (p.Tyr575His) results in a conservative amino acid change located in the Zinc finger C2H2-type domain (IPR013087) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251450 control chromosomes (gnomAD). c.1723T>C has been reported in the literature in at least two individuals affected with Combined Pituitary Hormone Deficiency (CPHD; Babu_2019). These data indicate that the variant may be associated with disease. In vitro functional studies indicated that the variant significantly reduced GLI2 transcriptional activity (Babu_2019). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |