NM_005236.3(ERCC4):c.2395C>T (p.Arg799Trp) AND Xeroderma pigmentosum, group F

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Feb 22, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000018048.44

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]

Observations:

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

Recent activity

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Astarte castanea cytochrome oxidase 1 (COI) gene, partial cds; mitochondrial gen...
Astarte castanea cytochrome oxidase 1 (COI) gene, partial cds; mitochondrial gene for mitochondrial product
gi|18026505|gb|AF120662.1|

Nucleotide
Sepia officinalis isolate SOIM1H cytochrome c oxidase subunit I gene, partial cd...
Sepia officinalis isolate SOIM1H cytochrome c oxidase subunit I gene, partial cds; mitochondrial
gi|1761173804|gb|MN069250.1|

Nucleotide
Sepia officinalis isolate SOPP1H cytochrome c oxidase subunit I gene, partial cd...
Sepia officinalis isolate SOPP1H cytochrome c oxidase subunit I gene, partial cds; mitochondrial
gi|1761173802|gb|MN069249.1|

Nucleotide
TET16 tetraspanin [Arabidopsis thaliana]
TET16 tetraspanin [Arabidopsis thaliana]
Gene ID:838432

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038327	OMIM	no assertion criteria provided	Pathogenic (May 1, 1998)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8797827, 9579555
SCV000914705	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Dec 19, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21612988, 8797827, 20221251, 9579555 Citation Link,
SCV001499824	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 21, 2021)	maternal	clinical testing	PubMed (10) [See all records that cite these PMIDs] 24728327, 29105242, 28767289, 27528516, 28678401, 21228398, 29403087, 28431612, 8797827, 25741868
SCV002012437	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Pathogenic (Oct 28, 2021)	germline	clinical testing	Citation Link,
SCV002580798	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002587792	Wangler Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8797827, 27528516, 9579555, 20221251, 25741868
SCV002764685	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Aug 17, 2020)	germline	clinical testing	Citation Link,
SCV003841218	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Caucasians	maternal	yes	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.

Gregg SQ, Robinson AR, Niedernhofer LJ.

DNA Repair (Amst). 2011 Jul 15;10(7):781-91. doi: 10.1016/j.dnarep.2011.04.026. Epub 2011 May 25. Review.

PubMed [citation]

PMID:: 21612988
PMCID:: PMC3139823

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]

PMID:: 24728327
PMCID:: PMC3984285

See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000038327.3

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

Description

For discussion of the arg788-to-trp (R788W) mutation in the ERCC4 gene that was found in compound heterozygous state in a patient with xeroderma pigmentosum type F (XPF; 278760) by Sijbers et al. (1996), see 133520.0001.

Sijbers et al. (1998) found the R788W mutation in homozygous state in a second Caucasian patient with XPF. Mild ocular photophobia had been present from childhood, and acute skin reactions occurred upon exposure to sunlight. Basal and squamous cell carcinomas developed after his twenty-seventh year. In his late forties, progressive neurologic symptoms emerged, which included intellectual decline, mild chorea and ataxia, and marked cerebral and cerebellar atrophy. Sijbers et al. (1998) stated that such neurologic abnormalities were unusual in XPF, having been described in only 1 of 17 other XPF individuals. The patient's 5-fold reduced activity of nucleotide excision repair in cultured cells, combined with moderately affected cell survival and DNA replication after UV exposure, was typical of XPF. Biochemical, genetic, and clinical data indicated the presence of considerable residual repair activity, strongly suggesting that the R788W mutation is leaky. The 2 Caucasian patients carrying this mutation were not known to be related.

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

From Illumina Laboratory Services, Illumina, SCV000914705.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Across a selection of the available literature, the ERCC4 c.2395C>T (p.Arg799Trp) variant has been identified in 11 probands with xeroderma pigmentosum including five in a homozygous state, four in a heterozygous state and two in a compound heterozygous state (Sijbers et al. 1996; Sijbers et al. 1998; Gregg et al. 2011). The p.Arg799Trp variant is reported at a frequency of 0.001 in the European American population of the Exome Sequencing Project. Functional rescue studies showed that the variant could only partially rescue the nuclear excision repair defect and that the variant protein mislocalized to the cytoplasm (Sijbers et al. 1998; Ahmad et al. 2010). Based on the collective evidence, the p.Arg799Trp variant is classified as pathogenic for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV001499824.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasians	2	not provided	not provided	clinical testing	PubMed (10)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	blood	not provided		2	not provided	1	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002012437.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ERCC4 c.2395C>T (p.Arg799Trp) missense change has a maximum subpopulation frequency of 0.081% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-14041848-C-T). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), and in vitro functional assays in LCLs (Epstein–Barr virus transformed lymphoblastoid cell lines) and fibroblasts have shown that this variant causes reduced protein expression of nuclear ERCC4 which is attributed to protein mislocalization and can result in decreased cell survival and DNA replication after ultraviolet light exposure (PS3; PMID: 20221251, 29105242, 9579555). This variant has been reported in over ten individuals affected with xeroderma pigmentosum (PS4, PM3; PMID: 8797827, 9579555, 23623389, 21228398, 28431612, 29892709). In addition, it has been reported in three individuals with autosomal recessive cerebellar ataxia with mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn (PMID: 29403087), one individual with sporadic ataxia (PMID: 31692161), two individuals with head and neck squamous cell carcinoma (PMID: 28678401), one individual with sporadic pancreatic adenocarcinoma (PMID: 28767289), one individual with Cockayne syndrome (PMID: 29105242), and one individual with colorectal cancer (PMID: 31871297). This variant is also known as p.Arg788Trp in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied: PS3, PS4, PM3, PP3.

#	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 MGZ Medical Genetics Center, SCV002580798.1

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

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

From Wangler Lab, Baylor College of Medicine, SCV002587792.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (5)

Description

This missense ERCC4 variant at c.2395C>T (p.R799W) was seen on exome through the Texome project (R01HG011795). This variant has been described in individuals with ERCC4-related conditions (PMID: 8797827, 9579555, 20221251, 27528516). It has been observed in gnomAD with a frequency of 0.040% in the heterozygous state and has not been observed in the homozygous state (PM2). Functional studies suggest this variant is functionally defective (PMID: 9579555, 20221251) (PS3).This variant is predicted to be deleterious (CADD: 31.000) (PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic.

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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764685.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

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

From Baylor Genetics, SCV003841218.1

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

#	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: Nov 3, 2024

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