Submissions for variant NM_000168.6(GLI3):c.1622C>T (p.Thr541Met)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000855672	SCV000902261	likely pathogenic	Hyperreflexia; Ptosis; Postaxial hand polydactyly; Umbilical hernia; Babinski sign; Polysyndactyly of hallux; Basilar invagination; Short palpebral fissure		criteria provided, single submitter	clinical testing	Analysis of the data showed a novel heterozygous sequence variant in GLI3 gene. It is predicted as pathogenic by MutationTaster. This variant is classified as likely pathogenic which shows strong evidence of pathogenicity according to ACMG guidelines (Richards et al., 2015). Sanger sequencing confirmed the variation.
Invitae	RCV001204667	SCV001375883	likely pathogenic	Greig cephalopolysyndactyly syndrome; Pallister-Hall syndrome	2019-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 541 of the GLI3 protein (p.Thr541Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Greig cephalopolysyndactyly syndrome (Invitae). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV001266774	SCV001444953	uncertain significance	Inborn genetic diseases	2015-03-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002067220	SCV002497510	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing

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