NM_000123.4(ERCC5):c.1173dup (p.Lys392Ter) AND Xeroderma pigmentosum

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 7, 2024
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:: RCV000605921.6

Allele description [Variation Report for NM_000123.4(ERCC5):c.1173dup (p.Lys392Ter)]

NM_000123.4(ERCC5):c.1173dup (p.Lys392Ter)

Genes:

BIVM-ERCC5:BIVM-ERCC5 readthrough [Gene - HGNC]
ERCC5:ERCC excision repair 5, endonuclease [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

13q33.1

Genomic location:

Preferred name:

NM_000123.4(ERCC5):c.1173dup (p.Lys392Ter)

Other names:

NM_000123.3:c.1173dupT

HGVS:

NC_000013.11:g.102862322dup
NG_007146.1:g.21499dup
NM_000123.4:c.1173dupMANE SELECT
NM_001204425.2:c.2535dup
NP_000114.2:p.Lys392Terfs
NP_000114.3:p.Lys392Ter
NP_001191354.2:p.Lys846Ter
LRG_464t1:c.1173dup
LRG_464:g.21499dup
LRG_464p1:p.Lys392Terfs
NC_000013.10:g.103514672_103514673insT
NC_000013.10:g.103514672dup
NM_000123.3:c.1173_1174insT
NM_000123.3:c.1173dup
NM_000123.4:c.1173dupTMANE SELECT
p.Lys392X

Protein change:

K392*

Links:

dbSNP: rs1283214655

NCBI 1000 Genomes Browser:

rs1283214655

Molecular consequence:

NM_000123.4:c.1173dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001204425.2:c.2535dup - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Xeroderma pigmentosum (XP)
Synonyms:: Xeroderma pigmentosa
Identifiers:: MONDO: MONDO:0019600; MedGen: C0043346

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000731381	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Mar 4, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005040090	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000731381

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Mar 4, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005040090

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 7, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Expansion of the genotypic and phenotypic spectrum of xeroderma pigmentosum in Chinese population.

Zhang J, Cheng R, Yu X, Sun Z, Li M, Yao Z.

Photodermatol Photoimmunol Photomed. 2017 Jan;33(1):58-63. doi: 10.1111/phpp.12283.

PubMed [citation]

PMID:: 27982466

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731381.1

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

Description

The p.Lys392X (NM_000123.3 c.1173dup) variant in ERCC5 has not been previously r eported in individuals with xeroderma pigmentosum and was absent from large popu lation studies. This variant is predicted to cause a frameshift, which alters th e protein?s amino acid sequence and leads to a premature termination codon at po sition 392. This alteration is then predicted to lead to a truncated or absent p rotein. Biallelic loss of function in ERCC5 has been associated with xeroderma p igmentosum. In summary, although additional studies are required to fully establ ish a null effect on the protein, the p.Lys392X variant in ERCC5 is likely patho genic for xeroderma pigmentosum in an autosomal recessive manner based upon its predicted functional impact.

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005040090.2

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

Description

Variant summary: ERCC5 c.1173dupT (p.Lys392X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251034 control chromosomes. c.1173dupT has been reported in the literature at a compound heterozygous state with a second pathogenic variant in at-least one individual affected with Xeroderma Pigmentosum (example, Zhang_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27982466). ClinVar contains an entry for this variant (Variation ID: 517221). Based on the evidence outlined above, the variant was 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

Last Updated: Sep 1, 2024

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