Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000823902 | SCV000964773 | uncertain significance | Holoprosencephaly 9; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome | 2023-04-20 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 665586). 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. 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 GLI2 protein function. This missense change has been observed in individual(s) with holoprosencephaly (HPE) (PMID: 21416594). This variant is present in population databases (rs766283583, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 226 of the GLI2 protein (p.Arg226His). |
Illumina Laboratory Services, |
RCV001135701 | SCV001295494 | uncertain significance | Holoprosencephaly 9 | 2017-04-28 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Prevention |
RCV003928289 | SCV004741233 | uncertain significance | GLI2-related condition | 2023-12-13 | criteria provided, single submitter | clinical testing | The GLI2 c.677G>A variant is predicted to result in the amino acid substitution p.Arg226His. This variant has been reported along with a variant in ZIC2 in an individual with holoprosencephaly; However, the mother and sibling of this individual also harbored both the GLI2 and ZIC2 variants and had no evidence of holoprosencephaly (Wannasilp et al. 2011. PubMed ID: 21416594). It has been classified as likely benign in a variant interpretation study (Table 2, Corder et al. 2021. PubMed ID: 34921505). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |