NM_000168.6(GLI3):c.1874G>A (p.Arg625Gln) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 30, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000634035.7

Allele description [Variation Report for NM_000168.6(GLI3):c.1874G>A (p.Arg625Gln)]

NM_000168.6(GLI3):c.1874G>A (p.Arg625Gln)

Gene:

GLI3:GLI family zinc finger 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p14.1

Genomic location:

Preferred name:

NM_000168.6(GLI3):c.1874G>A (p.Arg625Gln)

HGVS:

NC_000007.14:g.41972566C>T
NG_008434.1:g.269454G>A
NM_000168.6:c.1874G>AMANE SELECT
NP_000159.3:p.Arg625Gln
NC_000007.13:g.42012165C>T
NM_000168.5:c.1874G>A

Protein change:

R625Q

Links:

dbSNP: rs1554306094

NCBI 1000 Genomes Browser:

rs1554306094

Molecular consequence:

NM_000168.6:c.1874G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Greig cephalopolysyndactyly syndrome (GCPS)
Synonyms:: Greig syndrome; Polysyndactyly with peculiar skull shape
Identifiers:: MONDO: MONDO:0008287; MedGen: C0265306; Orphanet: 380; OMIM: 175700

Name:: Pallister-Hall syndrome (PHS)
Synonyms:: Hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly
Identifiers:: MONDO: MONDO:0007804; MedGen: C0265220; Orphanet: 672; OMIM: 146510

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000755313	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 30, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15739154, 24736735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000755313

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 30, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, Abbott MH, Aughton DJ, Aylsworth AS, Bamshad MJ, Booth C, Curry CJ, David A, Dinulos MB, Flannery DB, Fox MA, Graham JM, Grange DK, Guttmacher AE, Hannibal MC, Henn W, Hennekam RC, et al.

Am J Hum Genet. 2005 Apr;76(4):609-22. Epub 2005 Feb 28.

PubMed [citation]

PMID:: 15739154
PMCID:: PMC1199298

New insights into genotype-phenotype correlation for GLI3 mutations.

Démurger F, Ichkou A, Mougou-Zerelli S, Le Merrer M, Goudefroye G, Delezoide AL, Quélin C, Manouvrier S, Baujat G, Fradin M, Pasquier L, Megarbané A, Faivre L, Baumann C, Nampoothiri S, Roume J, Isidor B, Lacombe D, Delrue MA, Mercier S, Philip N, Schaefer E, et al.

Eur J Hum Genet. 2015 Jan;23(1):92-102. doi: 10.1038/ejhg.2014.62. Epub 2014 Apr 16.

PubMed [citation]

PMID:: 24736735
PMCID:: PMC4266745

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000755313.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg625Trp) has been determined to be pathogenic (PMID: 15739154). This suggests that the arginine residue is critical for GLI3 protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported in the literature in individuals affected with Greig Cephalopolysyndactyly syndrome (PMID: 15739154, 24736735), and at least one of them has been confirmed to be de novo (PMID: 24736735). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 625 of the GLI3 protein (p.Arg625Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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