ClinVar Genomic variation as it relates to human health
NM_003722.5(TP63):c.955C>T (p.Arg319Cys)
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_003722.5(TP63):c.955C>T (p.Arg319Cys)
Variation ID: 6532 Accession: VCV000006532.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q28 3: 189867905 (GRCh38) [ NCBI UCSC ] 3: 189585694 (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 Jan 8, 2018 Feb 14, 2024 Apr 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003722.5:c.955C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003713.3:p.Arg319Cys missense NM_001114980.2:c.673C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001108452.1:p.Arg225Cys missense NM_001114978.2:c.955C>T NP_001108450.1:p.Arg319Cys missense NM_001114979.2:c.955C>T NP_001108451.1:p.Arg319Cys missense NM_001114981.2:c.673C>T NP_001108453.1:p.Arg225Cys missense NM_001114982.2:c.673C>T NP_001108454.1:p.Arg225Cys missense NM_001329144.2:c.955C>T NP_001316073.1:p.Arg319Cys missense NM_001329145.2:c.673C>T NP_001316074.1:p.Arg225Cys missense NM_001329146.2:c.418C>T NP_001316075.1:p.Arg140Cys missense NM_001329148.2:c.955C>T NP_001316077.1:p.Arg319Cys missense NM_001329149.2:c.673C>T NP_001316078.1:p.Arg225Cys missense NM_001329150.2:c.418C>T NP_001316079.1:p.Arg140Cys missense NM_001329964.2:c.949C>T NP_001316893.1:p.Arg317Cys missense NC_000003.12:g.189867905C>T NC_000003.11:g.189585694C>T NG_007550.3:g.276160C>T LRG_428:g.276160C>T LRG_428t1:c.955C>T LRG_428p1:p.Arg319Cys Q9H3D4:p.Arg319Cys - Protein change
- R319C, R140C, R317C, R225C
- Other names
- R280C
- Canonical SPDI
- NC_000003.12:189867904:C:T
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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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TP63 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
686 | 747 |
Conditions - Germline
Condition
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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
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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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Jul 1, 2000 | RCV000006905.3 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 5, 2022 | RCV001280776.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2023 | RCV002512857.2 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003162215.2 |
Submissions - Germline
Classification
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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
(Sep 28, 2020)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV001468099.1
First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021 |
Comment on evidence:
PS3, PS4, PP1, PP3, PM1, PM2
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Pathogenic
(Nov 14, 2019)
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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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Blueprint Genetics
Accession: SCV001832271.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Comment:
Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003853247.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
A Heterozygous Missense variant c.955C>T in Exon 7 of the TP63 gene that results in the amino acid substitution p.Arg319Cys was identified. The observed variant … (more)
A Heterozygous Missense variant c.955C>T in Exon 7 of the TP63 gene that results in the amino acid substitution p.Arg319Cys was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. . ClinVar has also classified this variant as Pathogenic (Variant ID: 6532). The observed variant previously been reported in the patient affected with ectrodactyly (Ianakiev P et. al 2000). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Dec 15, 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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Revvity Omics, Revvity
Accession: SCV003820391.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Apr 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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TP63-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003525392.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP63 function (PMID: 18626511). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP63 function (PMID: 18626511). 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: 6532). This variant is also known as 982T->C, R280C. This missense change has been observed in individual(s) with clinical features of ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome (PMID: 10839977, 12161593, 21211247, 31050217). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 319 of the TP63 protein (p.Arg319Cys). (less)
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Pathogenic
(Jul 05, 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: SCV002015680.3
First in ClinVar: Nov 20, 2021 Last updated: Mar 04, 2023 |
Comment:
Identified in multiple individuals with TP63-related disorders referred for genetic testing at GeneDx and in published literature (Ianakiev et al., 2000; Yang et al., 2017); … (more)
Identified in multiple individuals with TP63-related disorders referred for genetic testing at GeneDx and in published literature (Ianakiev et al., 2000; Yang et al., 2017); Published functional studies demonstrate interference with TP63 protein function and inhibition of the wild-type protein in a dominant-negative manner (Khokhar et al., 2008; Serra et al., 2011); 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; This variant is associated with the following publications: (PMID: 22574117, 24460914, 12161593, 22069181, 29620206, 21211247, 15324320, 31050217, 28420484, 18626511, 10839977, 17224651, 21652629) (less)
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Pathogenic
(Jul 01, 2000)
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no assertion criteria provided
Method: literature only
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SPLIT-HAND/FOOT MALFORMATION 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027101.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 08, 2018 |
Comment on evidence:
In a family of mixed ancestry from Cape Province, South Africa, with split-hand/foot malformation (SHFM4; 605289), Ianakiev et al. (2000) identified a 982T-C transition in … (more)
In a family of mixed ancestry from Cape Province, South Africa, with split-hand/foot malformation (SHFM4; 605289), Ianakiev et al. (2000) identified a 982T-C transition in exon 7 of the TP63 gene, predicted to cause an arg280-to-cys (R280C) amino acid substitution. The phenotype in this family, designated A, ranged from severe 'lobster claw' malformations of the feet in 1 individual, to minor 3/4 syndactyly of the left foot appearing as the only manifestation in another individual. The daughter of the latter individual had distal duplications of her thumbs bilaterally with absence of the second and third phalanges of the right hand and an absent second phalanx with 3/4 syndactyly of the left hand. No members of the family had significant abnormality of the face, palate, skin, teeth, hair, or nails. No abnormalities of the mammary glands or nipples were noted. (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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Tooth defects of EEC and AEC syndrome caused by heterozygous TP63 mutations in three Chinese families and genotype-phenotype correlation analyses of TP63-related disorders. | Zheng J | Molecular genetics & genomic medicine | 2019 | PMID: 31050217 |
[Heterozygous TP63 mutation in a Chinese patient with ectrodactyly-ectodermal dysplasia clefting syndrome without clefting]. | Han D | Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology | 2010 | PMID: 21211247 |
Differential effects of p63 mutants on transactivation of p53 and/or p63 responsive genes. | Khokhar SK | Cell research | 2008 | PMID: 18626511 |
Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. | Barrow LL | Journal of medical genetics | 2002 | PMID: 12161593 |
Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. | Ianakiev P | American journal of human genetics | 2000 | PMID: 10839977 |
Text-mined citations for rs121908839 ...
HelpRecord last updated May 08, 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.