ClinVar Miner

Submissions for variant NM_000168.6(GLI3):c.2119C>T (p.Pro707Ser) (rs121917716)

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Total submissions: 7
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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 uncertain significance Greig cephalopolysyndactyly syndrome; Pallister-Hall syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 707 of the GLI3 protein (p.Pro707Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs121917716, ExAC 0.03%). This variant has been reported in an individual affected with Greig syndrome (PMID: 9302279). ClinVar contains an entry for this variant (Variation ID: 13831). An experimental study has shown that this missense change partially disrupts the nuclear localization of GLI3 and reduces its transcriptional activity in a reporter assay (PMID: 19829694). In summary, this variant is a rare missense change that partially disrupts protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000782254 SCV001800972 uncertain significance not provided 2021-06-01 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: 27535533, 9302279, 10441570, 10441342, 29601828, 19829694)
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 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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