VCV001677244.2 - ClinVar

NM_003722.5(TP63):c.1939C>T (p.Arg647Cys)

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.

(2)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003722.5(TP63):c.1939C>T (p.Arg647Cys)

Variation ID: 1677244 Accession: VCV001677244.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q28 3: 189894398 (GRCh38) [ NCBI UCSC ] 3: 189612187 (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	Oct 22, 2022	Apr 9, 2023	Apr 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003722.5:c.1939C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003713.3:p.Arg647Cys	missense
NM_001114980.2:c.1657C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001108452.1:p.Arg553Cys	missense
NM_001114978.2:c.*177C>T		3 prime UTR
NM_001114981.2:c.*177C>T		3 prime UTR
NM_001329144.2:c.*167C>T		3 prime UTR
NM_001329145.2:c.*167C>T		3 prime UTR
NM_001329146.2:c.1402C>T	NP_001316075.1:p.Arg468Cys	missense
NM_001329148.2:c.1927C>T	NP_001316077.1:p.Arg643Cys	missense
NM_001329149.2:c.*167C>T		3 prime UTR
NM_001329150.2:c.*167C>T		3 prime UTR
NM_001329964.2:c.1933C>T	NP_001316893.1:p.Arg645Cys	missense
NC_000003.12:g.189894398C>T
NC_000003.11:g.189612187C>T
NG_007550.3:g.302653C>T
LRG_428:g.302653C>T
LRG_428t1:c.1939C>T	LRG_428p1:p.Arg647Cys

... more HGVS ... less HGVS

Protein change

R468C, R553C, R643C, R645C, R647C

Other names

Canonical SPDI

NC_000003.12:189894397: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.

Links

OMIM: 603273.0033 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	697	759

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.
Premature ovarian insufficiency	Pathogenic (1)	no assertion criteria provided	Mar 1, 2022	RCV002291804.1
Premature ovarian failure 21	Pathogenic (1)	no assertion criteria provided	Apr 4, 2023	RCV003159547.1

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 (Mar 01, 2022)	no assertion criteria provided Method: research	Premature ovarian insufficiency Affected status: yes Allele origin: unknown	Reproductive Development, Murdoch Childrens Research Institute Accession: SCV002500836.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022
Pathogenic (Apr 04, 2023)	no assertion criteria provided Method: literature only	PREMATURE OVARIAN FAILURE 21 Affected status: not provided Allele origin: germline	OMIM Accession: SCV003853266.1 First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023	Publications: PubMed (2) PubMed: 35801529‚ 36856110 Comment on evidence: In a 27-year-old woman with secondary amenorrhea and atrophic ovaries devoid of follicles (POF21; 620311), Tucker et al. (2022) identified heterozygosity for a paternally inherited … (more) In a 27-year-old woman with secondary amenorrhea and atrophic ovaries devoid of follicles (POF21; 620311), Tucker et al. (2022) identified heterozygosity for a paternally inherited c.1939C-T transition (c.1939C-T, NM_003722.5) in exon 14 of the TP63 gene, resulting in an arg647-to-cys (R647C) substitution at a highly conserved residue within the C-terminal TID. The mutation was not found in the gnomAD database. Analysis of the TP63 complex conformation using BN-PAGE showed that the R647C substitution disrupts TP63 dimerization, causing an open active tetramer conformation. Luciferase reporter assays revealed a significant increase in transcriptional activity with the R97P mutant compared to wildtype TP63. In 3 unrelated Chinese women (patients 8, 9, and 10) with secondary amenorrhea and nonvisualization of the ovaries on ultrasound, Huang et al. (2023) identified heterozygosity for the R647C mutation in the TP63 gene. The R647C variant was not found in the ExAC database, but was present at low minor allele frequency in gnomAD (MAF, 0.00001316). Western blot of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but significantly reduced expression of the R647C mutant. BN-PAGE analysis suggested that the R647C mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the R647C mutant. Mice heterozygous for the R647C mutation showed accelerated oocyte loss, reduced fertility, and impaired oocyte quality, but the phenotypes were less severe than mice carrying a mutation that truncated the TID. The authors noted that this was consistent with patients carrying the R647C mutation presenting with secondary amenorrhea. (less)

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

Title	Author	Journal	Year	Link
TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.	Huang C	The Journal of clinical investigation	2023	PMID: 36856110
Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.	Tucker EJ	Human mutation	2022	PMID: 35801529

Text-mined citations for this variant ...

Record last updated Dec 02, 2023

ClinVar Genomic variation as it relates to human health

NM_003722.5(TP63):c.1939C>T (p.Arg647Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...