NM_000168.6(GLI3):c.3365_3366del (p.Val1122fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 26, 2020
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:: RCV001388671.7

Allele description [Variation Report for NM_000168.6(GLI3):c.3365_3366del (p.Val1122fs)]

NM_000168.6(GLI3):c.3365_3366del (p.Val1122fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

7p14.1

Genomic location:

Preferred name:

NM_000168.6(GLI3):c.3365_3366del (p.Val1122fs)

HGVS:

NC_000007.14:g.41965708_41965709del
NG_008434.1:g.276313_276314del
NM_000168.6:c.3365_3366delMANE SELECT
NP_000159.3:p.Val1122fs
NC_000007.13:g.42005305_42005306del
NC_000007.13:g.42005306_42005307del

Protein change:

V1122fs

Links:

dbSNP: rs2128705693

NCBI 1000 Genomes Browser:

rs2128705693

Molecular consequence:

NM_000168.6:c.3365_3366del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001589745	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 26, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24736735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001589745

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 26, 2020)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001589745.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GLI3 protein. Other variant(s) that disrupt this region (p.Thr1488Lysfs*23) have been determined to be pathogenic (PMID: 24736735). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with GLI3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the GLI3 gene (p.Val1122Alafs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 459 amino acids of the GLI3 protein.

#	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: Sep 29, 2024

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