Submissions for variant NM_000168.6(GLI3):c.2119C>T (p.Pro707Ser)

gnomAD frequency: 0.00028  dbSNP: rs121917716

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000500441	SCV000594998	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000542657	SCV000630786	likely benign	Greig cephalopolysyndactyly syndrome; Pallister-Hall syndrome	2023-10-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000782254	SCV001800972	uncertain significance	not provided	2022-06-11	criteria provided, single submitter	clinical testing	Identified in an individual with Greig cephalopolysyndactyly syndrome (GCPS) and individuals without GCPS in published literature (Wild et al., 1997; Sribudiani et al., 2018); also observed in heterozygous state in several clinically unaffected individuals referred for genetic testing at GeneDx; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19829694, 29601828, 10441342, 10441570, 9302279, 27535533)
CeGaT Center for Human Genetics Tuebingen	RCV000782254	SCV004156803	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing
OMIM	RCV000014843	SCV000035098	pathogenic	Greig cephalopolysyndactyly syndrome	1997-10-01	no assertion criteria provided	literature only
Clinical Genetics, Erasmus University Medical Center	RCV000508658	SCV000328910	likely pathogenic	Hirschsprung disease, susceptibility to, 1	2016-11-18	no assertion criteria provided	clinical testing
Gharavi Laboratory, Columbia University	RCV000782254	SCV000920747	likely benign	not provided	2018-09-16	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000782254	SCV001548767	uncertain significance	not provided		no assertion criteria provided	clinical testing	The GLI3 p.Pro707Ser variant was identified in the literature in one of two patients with Greig cephalopolysyndactyly syndrome (Wild_1997_PMID:9302279). The variant was identified in dbSNP (ID: rs121917716), ClinVar (classified as a VUS by Invitae and Genetic Services Laboratory at University of Chicago, as likely pathogenic by Clinical Genetics at Erasmus University Medical Center and as likely benign by Gharavi Laboratory at Columbia University), Cosmic (FATHMM prediction: pathogenic; score=0.97) and LOVD 3.0 (classified as a VUS, likely pathogenic and pathogenic). The variant was also identified in control databases in 73 of 282622 chromosomes at a frequency of 0.000258 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 65 of 128924 chromosomes (freq: 0.000504), Other in 2 of 7228 chromosomes (freq: 0.000277), Latino in 5 of 35440 chromosomes (freq: 0.000141) and African in 1 of 24970 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The p.Pro707 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) 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 (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.