Submissions for variant NM_001374353.1(GLI2):c.1370G>A (p.Trp457Ter)

dbSNP: rs1553476382

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594134	SCV000703609	pathogenic	not provided	2016-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000594134	SCV001874736	pathogenic	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV000594134	SCV002024847	pathogenic	not provided	2020-03-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854023	SCV002242660	pathogenic	Holoprosencephaly 9; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp474*) in the GLI2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLI2 are known to be pathogenic (PMID: 20685856, 24744436). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLI2-related conditions. ClinVar contains an entry for this variant (Variation ID: 498545). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004984993	SCV005596390	pathogenic	Inborn genetic diseases	2024-09-18	criteria provided, single submitter	clinical testing	The c.1421G>A (p.W474*) alteration, located in exon 9 (coding exon 9) of the GLI2 gene, consists of a G to A substitution at nucleotide position 1421. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 474. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001854023	SCV005650866	likely pathogenic	Holoprosencephaly 9; Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	2024-02-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915705	SCV004729979	pathogenic	GLI2-related disorder	2024-02-16	no assertion criteria provided	clinical testing	The GLI2 c.1421G>A variant is predicted to result in premature protein termination (p.Trp474*). To our knowledge, this variant has not been reported in the literature or public population databases. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/498545/). Furthermore, loss of function variants in the GLI2 gene are associated with holoprosencephaly (Roessler et al. 2003. PubMed ID: 14581620; Dubourg et al. 2016. PubMed ID: 27363716). In summary, we interpret this variant as pathogenic.