VCV000006528.9 - ClinVar

NM_003722.5(TP63):c.728G>A (p.Arg243Gln)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003722.5(TP63):c.728G>A (p.Arg243Gln)

Variation ID: 6528 Accession: VCV000006528.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q28 3: 189864380 (GRCh38) [ NCBI UCSC ] 3: 189582169 (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 8, 2018	Feb 14, 2024	Jun 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003722.5:c.728G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003713.3:p.Arg243Gln	missense
NM_001114980.2:c.446G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001108452.1:p.Arg149Gln	missense
NM_001114978.2:c.728G>A	NP_001108450.1:p.Arg243Gln	missense
NM_001114979.2:c.728G>A	NP_001108451.1:p.Arg243Gln	missense
NM_001114981.2:c.446G>A	NP_001108453.1:p.Arg149Gln	missense
NM_001114982.2:c.446G>A	NP_001108454.1:p.Arg149Gln	missense
NM_001329144.2:c.728G>A	NP_001316073.1:p.Arg243Gln	missense
NM_001329145.2:c.446G>A	NP_001316074.1:p.Arg149Gln	missense
NM_001329146.2:c.191G>A	NP_001316075.1:p.Arg64Gln	missense
NM_001329148.2:c.728G>A	NP_001316077.1:p.Arg243Gln	missense
NM_001329149.2:c.446G>A	NP_001316078.1:p.Arg149Gln	missense
NM_001329150.2:c.191G>A	NP_001316079.1:p.Arg64Gln	missense
NM_001329964.2:c.722G>A	NP_001316893.1:p.Arg241Gln	missense
NC_000003.12:g.189864380G>A
NC_000003.11:g.189582169G>A
NG_007550.3:g.272635G>A
LRG_428:g.272635G>A
LRG_428t1:c.728G>A	LRG_428p1:p.Arg243Gln
	Q9H3D4:p.Arg243Gln

... more HGVS ... less HGVS

Protein change

R243Q, R149Q, R241Q, R64Q

Other names

R204Q

Canonical SPDI

NC_000003.12:189864379: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.

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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

UniProtKB: Q9H3D4#VAR_020870 OMIM: 603273.0002 dbSNP: rs121908836 ClinGen: CA118335 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.
TP63		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	701	763

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.
Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	Pathogenic (1)	no assertion criteria provided	Oct 15, 1999	RCV000006901.3
TP63-Related Spectrum Disorders	Pathogenic (1)	criteria provided, single submitter	Jun 10, 2023	RCV000705452.7
Split hand-foot malformation 4	Pathogenic (1)	criteria provided, single submitter	May 22, 2022	RCV002250454.1
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2021	RCV001804714.2

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.
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Split hand-foot malformation 4 Affected status: yes Allele origin: germline	3billion Accession: SCV002520998.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006528). A different missense change at the same codon (p.Arg243Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006527). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Syndactyly (present)
Pathogenic (Dec 27, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002050585.2 First in ClinVar: Jan 08, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more) Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31050217, 10535733, 28293528, 12939657, 29620206, 26075610, 17224651, 21652629, 33471964, 34401172, 34906519) (less)
Pathogenic (Jun 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	TP63-Related Spectrum Disorders Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000834450.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 28492532‚ 10535733‚ 12525544‚ 18626511‚ 18792980‚ 20543567‚ 21078104‚ 21652629‚ 23355676‚ 23463580‚ 28293528‚ 29620206 Comment: This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the … (more) This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg243 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10535733, 12525544, 18626511, 18792980, 20543567, 21078104, 21652629, 23355676, 23463580). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP63 protein function. ClinVar contains an entry for this variant (Variation ID: 6528). This variant is also known as p.Arg204Gln. This missense change has been observed in individual(s) with autosomal dominant split-hand-split-foot malformation or SHFM and ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome (PMID: 10535733, 28293528, 29620206). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 243 of the TP63 protein (p.Arg243Gln). (less)
Pathogenic (Oct 15, 1999)	no assertion criteria provided Method: literature only	ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027097.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 08, 2018	Publications: PubMed (1) PubMed: 10535733 Comment on evidence: In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous arg204-to-gln mutation in the core … (more) In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous arg204-to-gln mutation in the core element II of the DNA binding domain of TP63. The mutation segregated with the disease and was not found in normal controls. (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006528). A different missense change at the same codon (p.Arg243Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006527). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31050217, 10535733, 28293528, 12939657, 29620206, 26075610, 17224651, 21652629, 33471964, 34401172, 34906519)

Comment:

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg243 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10535733, 12525544, 18626511, 18792980, 20543567, 21078104, 21652629, 23355676, 23463580). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP63 protein function. ClinVar contains an entry for this variant (Variation ID: 6528). This variant is also known as p.Arg204Gln. This missense change has been observed in individual(s) with autosomal dominant split-hand-split-foot malformation or SHFM and ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome (PMID: 10535733, 28293528, 29620206). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 243 of the TP63 protein (p.Arg243Gln).

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
Genetic analysis of a congenital split‑hand/split‑foot malformation 4 pedigree.	Yang X	Molecular medicine reports	2018	PMID: 29620206
Intermediate Phenotype between ADULT Syndrome and EEC Syndrome Caused by R243Q Mutation in TP63.	Otsuki Y	Plastic and reconstructive surgery. Global open	2016	PMID: 28293528
EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.	Monti P	Human mutation	2013	PMID: 23463580
APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations.	Shen J	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23355676
Differential altered stability and transcriptional activity of ΔNp63 mutants in distinct ectodermal dysplasias.	Browne G	Journal of cell science	2011	PMID: 21652629
ADULT syndrome caused by a mutation previously associated with EEC syndrome.	Avitan-Hersh E	Pediatric dermatology	2010	PMID: 21078104
The retinal dehydrogenase/reductase retSDR1/DHRS3 gene is activated by p53 and p63 but not by mutants derived from tumors or EEC/ADULT malformation syndromes.	Kirschner RD	Cell cycle (Georgetown, Tex.)	2010	PMID: 20543567
Split hand foot malformation with whorl-like pigmentary pattern: phenotypic expression of somatic mosaicism for the p63 mutation.	Kosaki R	American journal of medical genetics. Part A	2008	PMID: 18792980
Differential effects of p63 mutants on transactivation of p53 and/or p63 responsive genes.	Khokhar SK	Cell research	2008	PMID: 18626511
P63 mutations are not a major cause of non-syndromic split hand/foot malformation.	de Mollerat XJ	Journal of medical genetics	2003	PMID: 12525544
Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.	Celli J	Cell	1999	PMID: 10535733
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Text-mined citations for rs121908836 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_003722.5(TP63):c.728G>A (p.Arg243Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908836 ...