ClinVar Miner

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

gnomAD frequency: 0.00028  dbSNP: rs121917716
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Total submissions: 8
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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.

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