NM_005236.3(ERCC4):c.2395C>T (p.Arg799Trp) AND multiple conditions

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 30, 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:: RCV000467658.11

Allele description [Variation Report for NM_005236.3(ERCC4):c.2395C>T (p.Arg799Trp)]

NM_005236.3(ERCC4):c.2395C>T (p.Arg799Trp)

Gene:

ERCC4:ERCC excision repair 4, endonuclease catalytic subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.12

Genomic location:

Preferred name:

NM_005236.3(ERCC4):c.2395C>T (p.Arg799Trp)

Other names:

R788W

HGVS:

NC_000016.10:g.13947991C>T
NG_011442.1:g.32835C>T
NM_005236.3:c.2395C>TMANE SELECT
NP_005227.1:p.Arg799Trp
NP_005227.1:p.Arg799Trp
LRG_463t1:c.2395C>T
LRG_463:g.32835C>T
LRG_463p1:p.Arg799Trp
NC_000016.9:g.14041848C>T
NM_005236.2:c.2395C>T
Q92889:p.Arg799Trp
p.R799W

Protein change:

R799W; ARG788TRP

Links:

UniProtKB: Q92889#VAR_005850; OMIM: 133520.0002; OMIM: 133520.0011; dbSNP: rs121913049

NCBI 1000 Genomes Browser:

rs121913049

Molecular consequence:

NM_005236.3:c.2395C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Xeroderma pigmentosum, group F (XPF)
Synonyms:: XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F; XERODERMA PIGMENTOSUM VI; XP, GROUP F; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010215; MedGen: C0268140; OMIM: 278760

Name:: Cockayne syndrome
Synonyms:: Cockayne's syndrome; Dwarfism-retinal atrophy-deafness syndrome; Progeria-like syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0016006; MedGen: C0009207

Name:: Fanconi anemia complementation group Q
Identifiers:: MONDO: MONDO:0014108; MedGen: C3808988; Orphanet: 84; OMIM: 615272

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000548332	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 8797827, 23623389, 26074087, 27356891, 27528516, 28431612, 28678401, 28767289, 29105242, 29403087, 29892709, 9579555, 20221251, 28492532
SCV001749397	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000548332

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 30, 2023)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV001749397

GenomeConnect - Invitae Patient Insights Network

no classification provided

not provided

unknown

phenotyping only

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.

Sijbers AM, de Laat WL, Ariza RR, Biggerstaff M, Wei YF, Moggs JG, Carter KC, Shell BK, Evans E, de Jong MC, Rademakers S, de Rooij J, Jaspers NG, Hoeijmakers JH, Wood RD.

Cell. 1996 Sep 6;86(5):811-22.

PubMed [citation]

PMID:: 8797827

Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, Fawcett H, Wing JF, Lewin SO, Carr L, Li TS, Yoshiura K, Utani A, Hirano A, Yamashita S, Greenblatt D, Nardo T, Stefanini M, McGibbon D, Sarkany R, Fassihi H, Takahashi Y, et al.

Am J Hum Genet. 2013 May 2;92(5):807-19. doi: 10.1016/j.ajhg.2013.04.007. Epub 2013 Apr 25.

PubMed [citation]

PMID:: 23623389
PMCID:: PMC3644632

See all PubMed Citations (14)

Details of each submission

From Invitae, SCV000548332.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 799 of the ERCC4 protein (p.Arg799Trp). This variant is present in population databases (rs121913049, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ERCC4-related conditions (PMID: 8797827, 20221251, 23623389, 26074087, 27356891, 27528516, 28431612, 28678401, 28767289, 29105242, 29403087, 29892709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2377C>T, p.Arg788Trp. ClinVar contains an entry for this variant (Variation ID: 16580). 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 ERCC4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ERCC4 function (PMID: 9579555, 20221251). For these reasons, this variant has been classified as 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

From GenomeConnect - Invitae Patient Insights Network, SCV001749397.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Pathogenic and reported on 12-16-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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

Last Updated: May 12, 2024

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