Submissions for variant NM_001374353.1(GLI2):c.4509T>G (p.Asp1503Glu)

dbSNP: rs148902971

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002539254	SCV001020720	benign	Holoprosencephaly 9; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	2022-11-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001132634	SCV001292301	benign	Holoprosencephaly 9	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003938385	SCV004747721	benign	GLI2-related disorder	2019-06-28	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV004027899	SCV004876168	likely benign	Inborn genetic diseases	2021-10-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358627	SCV001554418	benign	not specified		no assertion criteria provided	clinical testing	The GLI2 p.D1520E variant was identified in one heterozygous proband with hyperactivity, neurotransmitter deficiency, development delay, and neuro regression (Abbas_2020). The variant was identified in dbSNP (ID: rs148902971) and ClinVar (classified as benign by Invitae and Illumina). The variant was identified in control databases in 180 of 251180 chromosomes (1 homozygous) at a frequency of 0.0007166, and was observed at the highest frequency in the South Asian population in 172 of 30616 chromosomes (freq: 0.005618) (Genome Aggregation Database March 6, 2019, v2.1.1). This frequency is greater than expected for the rare, autosomal dominant Culler-Jones syndrome and Holoprosencephaly 9 condition associated with GLI2 variants. The p.D1520 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.