ClinVar Genomic variation as it relates to human health
NM_000168.6(GLI3):c.2374C>T (p.Arg792Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000168.6(GLI3):c.2374C>T (p.Arg792Ter)
Variation ID: 13828 Accession: VCV000013828.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p14.1 7: 41967653 (GRCh38) [ NCBI UCSC ] 7: 42007251 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 29, 2016 Feb 28, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000168.6:c.2374C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000159.3:p.Arg792Ter nonsense NC_000007.14:g.41967653G>A NC_000007.13:g.42007251G>A NG_008434.1:g.274368C>T - Protein change
- R792*
- Other names
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- Canonical SPDI
- NC_000007.14:41967652:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GLI3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1114 | 1143 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Dec 15, 2007 | RCV000014840.27 | |
Pathogenic (3) |
criteria provided, single submitter
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Jan 31, 2022 | RCV000489344.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 15, 2023 | RCV001047666.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 29, 2022 | RCV001450016.4 |
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
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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
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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
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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. |
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Pathogenic
(Jul 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Polydactyly, postaxial, type A1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581000.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000577441.5
First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported previously in association with GLI3-related disorders (Kalff-Suske et al.,1999; Furniss et al., 2007; Jamsheer et al., 2012; Patel et al., 2016); Nonsense variant predicted … (more)
Reported previously in association with GLI3-related disorders (Kalff-Suske et al.,1999; Furniss et al., 2007; Jamsheer et al., 2012; Patel et al., 2016); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Functional studies indicate that this variant is susceptible to nonsense-mediated mRNA decay (Furniss et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19308487, 34482537, 25525159, 10441342, 12794692, 15739154, 22903559, 19429598, 26508445, 18000979, 31306531, 30848202, 31573334) (less)
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Pathogenic
(May 31, 2021)
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criteria provided, single submitter
Method: research
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Polydactyly, postaxial, type A1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Additional submitter:
CUBI - Core Unit Bioinformatics, Berlin Institute of Health
Accession: SCV001653565.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Observation 1:
Sex: male
Tissue: Blood
Observation 2:
Sex: female
Tissue: Blood
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Polydactyly, postaxial, type A1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557498.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Greig cephalopolysyndactyly syndrome (MIM#175700) and Polydactyly, preaxial, type IV (MIM#174700). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 18000979). (I) 0201 - Variant has been shown to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction) (PMID: 18000979). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with Greig cephalopolysyndactyly syndrome (MIM#175700) and preaxial polydactyly type IV (MIM#174700) (PMID: 15739154, 18000979, 22903559, 26508445). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pallister-Hall syndrome
Greig cephalopolysyndactyly syndrome
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
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Invitae
Accession: SCV001211637.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg792*) in the GLI3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg792*) in the GLI3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLI3 are known to be pathogenic (PMID: 10441570, 15739154, 18000979, 24736735). This variant is present in population databases (rs121917714, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Greig cephalopolysyndactyly syndrome (PMID: 10441342, 12794692, 26508445). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13828). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 15, 2007)
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no assertion criteria provided
Method: literature only
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GREIG CEPHALOPOLYSYNDACTYLY SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035095.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
In a patient with Greig cephalopolysyndactyly syndrome (GCPS; 175700), Furniss et al. (2007) identified a heterozygous 2374C-T transition in exon 14 of the GLI3 gene, … (more)
In a patient with Greig cephalopolysyndactyly syndrome (GCPS; 175700), Furniss et al. (2007) identified a heterozygous 2374C-T transition in exon 14 of the GLI3 gene, resulting in an arg792-to-ter (R792X) substitution. The mutation was demonstrated to result in nonsense-mediated mRNA decay. Furniss et al. (2007) postulated that the relatively mild phenotype in this patient, which was less severe than that observed in Pallister-Hall syndrome (PHS; 146510), may be due to nonsense-mediated mRNA decay that eliminates a toxic dominant-negative effect of a mutant protein. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744369.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968908.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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GLI3 mutations in syndromic and non-syndromic polydactyly in two Indian families. | Patel R | Congenital anomalies | 2016 | PMID: 26508445 |
New insights into genotype-phenotype correlation for GLI3 mutations. | Démurger F | European journal of human genetics : EJHG | 2015 | PMID: 24736735 |
Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations. | Jamsheer A | Journal of applied genetics | 2012 | PMID: 22903559 |
Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3. | Furniss D | American journal of medical genetics. Part A | 2007 | PMID: 18000979 |
Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. | Johnston JJ | American journal of human genetics | 2005 | PMID: 15739154 |
Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. | Debeer P | American journal of medical genetics. Part A | 2003 | PMID: 12794692 |
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 | American journal of human genetics | 1999 | PMID: 10441570 |
Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. | Kalff-Suske M | Human molecular genetics | 1999 | PMID: 10441342 |
Text-mined citations for rs121917714 ...
HelpRecord last updated Mar 05, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.