NM_003722.5(TP63):c.1682G>A (p.Cys561Tyr) AND TP63-Related Spectrum Disorders

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 9, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002523954.3

Allele description [Variation Report for NM_003722.5(TP63):c.1682G>A (p.Cys561Tyr)]

NM_003722.5(TP63):c.1682G>A (p.Cys561Tyr)

Gene:

TP63:tumor protein p63 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q28

Genomic location:

Preferred name:

NM_003722.5(TP63):c.1682G>A (p.Cys561Tyr)

HGVS:

NC_000003.12:g.189890818G>A
NG_007550.3:g.299073G>A
NM_001114978.2:c.1652+1334G>A
NM_001114980.2:c.1400G>A
NM_001114981.2:c.1370+1334G>A
NM_001329144.2:c.1508-3388G>A
NM_001329145.2:c.1226-3388G>A
NM_001329146.2:c.1145G>A
NM_001329148.2:c.1670G>A
NM_001329149.2:c.1214-3388G>A
NM_001329150.2:c.959-3388G>A
NM_001329964.2:c.1676G>A
NM_003722.5:c.1682G>AMANE SELECT
NP_001108452.1:p.Cys467Tyr
NP_001316075.1:p.Cys382Tyr
NP_001316077.1:p.Cys557Tyr
NP_001316893.1:p.Cys559Tyr
NP_003713.3:p.Cys561Tyr
LRG_428t1:c.1682G>A
LRG_428:g.299073G>A
LRG_428p1:p.Cys561Tyr
NC_000003.11:g.189608607G>A
NM_003722.4:c.1682G>A

Protein change:

C382Y

Links:

dbSNP: rs1057518399

NCBI 1000 Genomes Browser:

rs1057518399

Molecular consequence:

NM_001114978.2:c.1652+1334G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001114981.2:c.1370+1334G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001329144.2:c.1508-3388G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001329145.2:c.1226-3388G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001329149.2:c.1214-3388G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001329150.2:c.959-3388G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001114980.2:c.1400G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001329146.2:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001329148.2:c.1670G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001329964.2:c.1676G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003722.5:c.1682G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: TP63-Related Spectrum Disorders
Identifiers:: MedGen: CN239305

Recent activity

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PREDICTED: Canis lupus dingo renin (REN), transcript variant X2, mRNA
PREDICTED: Canis lupus dingo renin (REN), transcript variant X2, mRNA
gi|2272654797|ref|XM_049107041.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003225869	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11159940, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003225869

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 9, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63.

McGrath JA, Duijf PH, Doetsch V, Irvine AD, de Waal R, Vanmolkot KR, Wessagowit V, Kelly A, Atherton DJ, Griffiths WA, Orlow SJ, van Haeringen A, Ausems MG, Yang A, McKeon F, Bamshad MA, Brunner HG, Hamel BC, van Bokhoven H.

Hum Mol Genet. 2001 Feb 1;10(3):221-9.

PubMed [citation]

PMID:: 11159940

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003225869.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant disrupts the p.Cys561 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11159940; Invitae). 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: 373405). This variant has not been reported in the literature in individuals affected with TP63-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 561 of the TP63 protein (p.Cys561Tyr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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