NM_000168.6(GLI3):c.827-2A>G AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 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:: RCV001379344.7

Allele description [Variation Report for NM_000168.6(GLI3):c.827-2A>G]

NM_000168.6(GLI3):c.827-2A>G

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.827-2A>G

HGVS:

NC_000007.14:g.42040241T>C
NG_008434.1:g.201779A>G
NG_008434.2:g.229027A>G
NM_000168.6:c.827-2A>GMANE SELECT
NC_000007.13:g.42079840T>C

Links:

dbSNP: rs2128738764

NCBI 1000 Genomes Browser:

rs2128738764

Molecular consequence:

NM_000168.6:c.827-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001577130	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 26, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 10441570, 15739154, 18000979, 24736735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577130

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 26, 2020)

germline

clinical testing

PubMed (6)
[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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations.

Radhakrishna U, Bornholdt D, Scott HS, Patel UC, Rossier C, Engel H, Bottani A, Chandal D, Blouin JL, Solanki JV, Grzeschik KH, Antonarakis SE.

Am J Hum Genet. 1999 Sep;65(3):645-55.

PubMed [citation]

PMID:: 10441570
PMCID:: PMC1377970

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577130.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GLI3 are known to be pathogenic (PMID: 10441570, 15739154, 18000979, 24736735). 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 affects an acceptor splice site in intron 6 of the GLI3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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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