Submissions for variant NM_001374353.1(GLI2):c.2657C>G (p.Thr886Ser)

gnomAD frequency: 0.00001  dbSNP: rs572826436

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000338365	SCV000338394	benign	not specified	2016-01-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000278618	SCV000416205	benign	Holoprosencephaly 9	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519181	SCV002990818	benign	Holoprosencephaly 9; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	2022-11-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518964	SCV003711944	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.
PreventionGenetics, part of Exact Sciences	RCV003940007	SCV004747685	likely benign	GLI2-related disorder	2019-06-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357538	SCV001553035	likely benign	not provided		no assertion criteria provided	clinical testing	The GLI2 p.T903S variant was not identified in the literature but was identified in dbSNP (ID: rs572826436) and ClinVar (classified as benign by EGL Genetic Diagnostics and Illumina). The variant was identified in control databases in 66 of 78370 chromosomes (1 homozygous) at a frequency of 0.0008422, and was observed at the highest frequency in the South Asian population in 65 of 15514 chromosomes (1 homozygous) (freq: 0.004190) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Thr903 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however this information is not predictive enough to assume 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.