ClinVar Genomic variation as it relates to human health
NM_001372066.1(TFAP2A):c.769A>G (p.Arg257Gly)
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_001372066.1(TFAP2A):c.769A>G (p.Arg257Gly)
Variation ID: 17937 Accession: VCV000017937.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p24.3 6: 10404509 (GRCh38) [ NCBI UCSC ] 6: 10404742 (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 Apr 4, 2013 Apr 15, 2024 Aug 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001372066.1:c.769A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001358995.1:p.Arg257Gly missense NM_001032280.3:c.745A>G NP_001027451.1:p.Arg249Gly missense NM_001042425.3:c.751A>G NP_001035890.1:p.Arg251Gly missense NR_145448.1:n.8T>C non-coding transcript variant NC_000006.12:g.10404509T>C NC_000006.11:g.10404742T>C NG_016151.1:g.20056A>G NG_075700.1:g.454T>C - Protein change
- R251G, R249G, R257G
- Other names
- R255G
- NM_003220.2:c.763A>G
- Canonical SPDI
- NC_000006.12:10404508:T:C
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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.
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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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LOC121740638 | - | - | - | GRCh38 | - | 84 |
TFAP2A | - | - |
GRCh38 GRCh37 |
130 | 254 | |
TFAP2A-AS2 | - | - | GRCh38 | - | 84 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2023 | RCV000019530.38 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV001090476.20 |
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
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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
(-)
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criteria provided, single submitter
Method: research
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Branchiooculofacial syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics
Accession: SCV000223994.1
First in ClinVar: Jun 20, 2015 Last updated: Jun 20, 2015 |
Clinical Features:
Cleft palate (present) , Cleft upper lip (present) , Dolichocephaly (present) , Branchial anomaly (present) , Strabismus (present) , Lacrimal duct stenosis (present) , Retinal … (more)
Cleft palate (present) , Cleft upper lip (present) , Dolichocephaly (present) , Branchial anomaly (present) , Strabismus (present) , Lacrimal duct stenosis (present) , Retinal coloboma (present) , Dilatated internal auditory canal (present) , Abnormality of the middle ear ossicles (present) , Bilateral conductive hearing impairment (present) (less)
Age: 0-9 years
Sex: male
Geographic origin: Russia
Method: Sanger sequencing
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Branchiooculofacial syndrome
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782345.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
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Likely pathogenic
(Oct 23, 2019)
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criteria provided, single submitter
Method: research
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Branchiooculofacial syndrome
Affected status: yes
Allele origin:
de novo
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV000993430.3 First in ClinVar: Sep 22, 2019 Last updated: Oct 30, 2020 |
Comment:
ACMG codes:PS2; PS4M; PM2; PP3
Number of individuals with the variant: 1
Clinical Features:
Intrauterine growth retardation (present) , Small for gestational age (present) , Congenital microcephaly (present) , Micrognathia (present) , Cleft lip (present) , Polyhydramnios (present)
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Pathogenic
(Jun 17, 2020)
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criteria provided, single submitter
Method: research
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Branchiooculofacial syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics
Accession: SCV001443809.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
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Pathogenic
(Mar 01, 2023)
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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: SCV003836870.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25622170, 25590586, 21250552, 21539471, 20358615, 23578821, 2004100, 10767004, 7747785, 18423521, 34930662, 34324503) (less)
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Pathogenic
(Aug 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Branchiooculofacial syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045867.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Retrognathia (present) , Hearing impairment (present) , Iris coloboma (present) , Short philtrum (present) , 4-5 toe syndactyly (present) , Posteriorly rotated ears (present)
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Likely pathogenic
(Mar 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Branchiooculofacial syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003811520.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002247267.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects TFAP2A function (PMID: 23578821). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 17937). This missense change has been observed in individuals with branchiooculofacial syndrome (PMID: 18423521, 20358615, 20461149, 21539471, 25590586). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 255 of the TFAP2A protein (p.Arg255Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. (less)
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Pathogenic
(May 01, 2017)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246047.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 01, 2010)
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no assertion criteria provided
Method: literature only
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BRANCHIOOCULOFACIAL SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039827.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In an 18-year-old man with branchiooculofacial syndrome (BOFS; 113620), previously studied by Lin et al. (2000), Milunsky et al. (2008) identified a de novo 10529A-G … (more)
In an 18-year-old man with branchiooculofacial syndrome (BOFS; 113620), previously studied by Lin et al. (2000), Milunsky et al. (2008) identified a de novo 10529A-G transition in exon 4 of the TFAP2A gene, resulting in an arg255-to-gly (R255G) substitution at a highly conserved residue in the basic region of the DNA-binding domain, a change that replaces a charged polar side chain with a nonpolar side chain with a predicted conformational space change. The mutation was not found in more than 300 controls. In a mother and daughter with BOFS, as well as an unrelated sporadic BOFS patient, Reiber et al. (2010) identified heterozygosity for the R255G mutation in the TFAP2A gene. Noting that R255G had been found in 3 of 11 unrelated mutation-positive patients, Reiber et al. (2010) suggested that it might represent a recurrent mutation causing BOFS. (less)
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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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A clinical and molecular analysis of branchio-oculo-facial syndrome patients in Russia revealed new mutations in TFAP2A. | Meshcheryakova TI | Annals of human genetics | 2015 | PMID: 25590586 |
Analysis of TFAP2A mutations in Branchio-Oculo-Facial Syndrome indicates functional complexity within the AP-2α DNA-binding domain. | Li H | Human molecular genetics | 2013 | PMID: 23578821 |
Craniofacial phenotype in the branchio-oculo-facial syndrome: four case reports. | Galliani E | The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association | 2012 | PMID: 21539471 |
Ocular manifestations of branchio-oculo-facial syndrome: report of a novel mutation and review of the literature. | Al-Dosari MS | Molecular vision | 2010 | PMID: 20461149 |
Additional clinical and molecular analyses of TFAP2A in patients with the branchio-oculo-facial syndrome. | Reiber J | American journal of medical genetics. Part A | 2010 | PMID: 20358615 |
TFAP2A mutations result in branchio-oculo-facial syndrome. | Milunsky JM | American journal of human genetics | 2008 | PMID: 18423521 |
Exclusion of the branchio-oto-renal syndrome locus (EYA1) from patients with branchio-oculo-facial syndrome. | Lin AE | American journal of medical genetics | 2000 | PMID: 10767004 |
Text-mined citations for rs121909574 ...
HelpRecord last updated Apr 20, 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.