VCV000599234.4 - ClinVar

NM_003221.4(TFAP2B):c.917C>T (p.Thr306Met)

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.

(4)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003221.4(TFAP2B):c.917C>T (p.Thr306Met)

Variation ID: 599234 Accession: VCV000599234.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.3 6: 50838070 (GRCh38) [ NCBI UCSC ] 6: 50805783 (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	Jan 5, 2019	Mar 11, 2023	Aug 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003221.4:c.917C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003212.2:p.Thr306Met	missense
NM_003221.3:c.917C>T
NC_000006.12:g.50838070C>T
NC_000006.11:g.50805783C>T
NG_008438.1:g.24345C>T

... more HGVS ... less HGVS

Protein change

T306M

Other names

Canonical SPDI

NC_000006.12:50838069:C:T

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

dbSNP: rs1232197674 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.
TFAP2B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	147	158

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.
Char syndrome	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Aug 16, 2022	RCV000735824.4

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 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.
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Char syndrome Affected status: yes Allele origin: unknown	Wangler Lab, Baylor College of Medicine Accession: SCV002577382.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Publications: PubMed (1) PubMed: 31012281 Comment: This missense TFAP2B variant at c.917C>T (p.T306M) was seen on exome through the Texome Project (R01HG011795). This variant was reported in an individual with Char … (more) This missense TFAP2B variant at c.917C>T (p.T306M) was seen on exome through the Texome Project (R01HG011795). This variant was reported in an individual with Char syndrome (PMID: 31012281). It has been observed in gnomAD with a frequency of <0.001%. This variant is predicted to be deleterious by multiple computational models (CADD: 29.600) (PP3). The evolutionary conservation of this residue is high. We classify this variant as a variant of uncertain significance. (less) Sex: male
Uncertain significance (Jun 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Char syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768876.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 11505339‚ 24507797‚ 31012281‚ 31292255 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative is a known mechanism of … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease in this gene and is associated with Char syndrome (MIM#169100) (PMID: 11505339). Loss of function is a likely mechanism of disease associated with patent ductus arteriosus 2 (MIM#617035) (PMID: 24507797). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. In a single family, the variant was inherited from an unaffected parent (PMID: 31292255). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31292255). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DNA binding domain (PMID: 31012281). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in one individual with Char syndrome as a de novo occurrence (MIM#169100) (PMID: 31012281). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Uncertain significance (Aug 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Char syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835256.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Likely pathogenic (Dec 19, 2018)	no assertion criteria provided Method: research	Char syndrome (Sporadic) Affected status: yes Allele origin: de novo	Gene Discovery Core-Manton Center, Boston Children's Hospital Accession: SCV000863561.1 First in ClinVar: Jan 05, 2019 Last updated: Jan 05, 2019

Comment:

This missense TFAP2B variant at c.917C>T (p.T306M) was seen on exome through the Texome Project (R01HG011795). This variant was reported in an individual with Char syndrome (PMID: 31012281). It has been observed in gnomAD with a frequency of <0.001%. This variant is predicted to be deleterious by multiple computational models (CADD: 29.600) (PP3). The evolutionary conservation of this residue is high. We classify this variant as a variant of uncertain significance.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease in this gene and is associated with Char syndrome (MIM#169100) (PMID: 11505339). Loss of function is a likely mechanism of disease associated with patent ductus arteriosus 2 (MIM#617035) (PMID: 24507797). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. In a single family, the variant was inherited from an unaffected parent (PMID: 31292255). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31292255). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DNA binding domain (PMID: 31012281). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in one individual with Char syndrome as a de novo occurrence (MIM#169100) (PMID: 31012281). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.	Timberlake AT	Proceedings of the National Academy of Sciences of the United States of America	2019	PMID: 31292255
A novel missense mutation in TFAP2B associated with Char syndrome and central diabetes insipidus.	Edward HL	American journal of medical genetics. Part A	2019	PMID: 31012281
Characterization of transcription factor AP-2 β mutations involved in familial isolated patent ductus arteriosus suggests haploinsufficiency.	Ji W	The Journal of surgical research	2014	PMID: 24507797
Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation.	Zhao F	American journal of human genetics	2001	PMID: 11505339

Text-mined citations for rs1232197674 ...

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 Mar 11, 2023

ClinVar Genomic variation as it relates to human health

NM_003221.4(TFAP2B):c.917C>T (p.Thr306Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1232197674 ...