VCV000037084.32 - ClinVar

NM_001374353.1(GLI2):c.4507G>A (p.Asp1503Asn)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001374353.1(GLI2):c.4507G>A (p.Asp1503Asn)

Variation ID: 37084 Accession: VCV000037084.32

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q14.2 2: 120990472 (GRCh38) [ NCBI UCSC ] 2: 121748048 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 2, 2016	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001374353.1:c.4507G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001361282.1:p.Asp1503Asn	missense
NM_001371271.1:c.4558G>A	NP_001358200.1:p.Asp1520Asn	missense
NM_001374354.1:c.4132G>A	NP_001361283.1:p.Asp1378Asn	missense
NM_005270.5:c.4558G>A	NP_005261.2:p.Asp1520Asn	missense
NC_000002.12:g.120990472G>A
NC_000002.11:g.121748048G>A
NG_009030.1:g.198182G>A
	P10070:p.Asp1520Asn

... more HGVS ... less HGVS

Protein change

D1520N, D1378N, D1503N

Other names

Canonical SPDI

NC_000002.12:120990471:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00459 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00459

1000 Genomes Project 30x 0.00484

Trans-Omics for Precision Medicine (TOPMed) 0.00910

The Genome Aggregation Database (gnomAD) 0.00964

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01092

Links

ClinGen: CA201056 UniProtKB: P10070#VAR_075217 OMIM: 165230.0007 dbSNP: rs114814747 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GLI2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1024	1053

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Holoprosencephaly 9	Likely benign (3)	criteria provided, single submitter	Apr 27, 2017	RCV000030731.31
not specified	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Feb 17, 2015	RCV000174553.10
Holoprosencephaly 9 Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	Benign (1)	criteria provided, single submitter	Jan 22, 2024	RCV000548311.11
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV001541226.15
Partial androgen insensitivity syndrome	Benign (1)	criteria provided, single submitter	May 4, 2023	RCV003993753.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310985.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Feb 17, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225871.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLI2 http://www.ncbi.nlm.nih.gov/vari… http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=2&from=121748048&to=121748048 Number of individuals with the variant: 1 Sex: mixed
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Holoprosencephaly 9 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000416239.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 22967285‚ 19223936‚ 21204792‚ 23408573 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jul 20, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001759199.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Comment: This variant is associated with the following publications: (PMID: 29165578, 21204792, 22967285)
Benign (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome Holoprosencephaly 9 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000655235.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005262758.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Partial androgen insensitivity syndrome Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812727.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: European Non-Finnish population allele frequency is 1.398% (rs114814747, 1841/128804 alleles, 11 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.2, … (more) European Non-Finnish population allele frequency is 1.398% (rs114814747, 1841/128804 alleles, 11 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.2, this variant is classified as BENIGN. Following criteria are met: BA1 (less)
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004149125.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: GLI2: BS1, BS2 Number of individuals with the variant: 12
Pathogenic (Jan 01, 2012)	no assertion criteria provided Method: literature only	HOLOPROSENCEPHALY 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000053392.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2017	Publications: PubMed (1) PubMed: 21204792 Comment on evidence: In a Brazilian girl with holoprosencephaly (HPE9; 610829), Bertolacini et al. (2012) identified a de novo heterozygous 4558G-A transition in the GLI2 gene, resulting in … (more) In a Brazilian girl with holoprosencephaly (HPE9; 610829), Bertolacini et al. (2012) identified a de novo heterozygous 4558G-A transition in the GLI2 gene, resulting in an asp1520-to-asn (D1520N) substitution. The mutation was not found in 96 Brazilian controls. At age 5 months, the child had a high forehead, facial asymmetry with hypoplastic left side, left-sided anophthalmia, abnormal ears, preauricular skin tags, and clefting. Reevaluation at age 3.5 years showed normal neuropsychologic development and normal CT images of the mastoid bone and brain. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	Holoprosencephaly 9 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734140.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799521.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924986.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928541.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

European Non-Finnish population allele frequency is 1.398% (rs114814747, 1841/128804 alleles, 11 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.2, this variant is classified as BENIGN. Following criteria are met: BA1

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency.	Flemming GM	The Journal of clinical endocrinology and metabolism	2013	PMID: 23408573
Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly.	França MM	Clinical endocrinology	2013	PMID: 22967285
Clinical findings in patients with GLI2 mutations--phenotypic variability.	Bertolacini CD	Clinical genetics	2012	PMID: 21204792
Characterization of two ectrodactyly-associated translocation breakpoints separated by 2.5 Mb on chromosome 2q14.1-q14.2.	David D	European journal of human genetics : EJHG	2009	PMID: 19223936
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLI2	-	-	-	-

Text-mined citations for rs114814747 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001374353.1(GLI2):c.4507G>A (p.Asp1503Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs114814747 ...