NM_000400.4(ERCC2):c.1996C>T (p.Arg666Trp) AND Cerebrooculofacioskeletal syndrome 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 3, 2023
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:: RCV003471050.3

Allele description [Variation Report for NM_000400.4(ERCC2):c.1996C>T (p.Arg666Trp)]

NM_000400.4(ERCC2):c.1996C>T (p.Arg666Trp)

Gene:

ERCC2:ERCC excision repair 2, TFIIH core complex helicase subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.32

Genomic location:

Preferred name:

NM_000400.4(ERCC2):c.1996C>T (p.Arg666Trp)

Other names:

p.Arg666Trp

HGVS:

NC_000019.10:g.45352556G>A
NG_007067.2:g.23032C>T
NM_000400.4:c.1996C>TMANE SELECT
NP_000391.1:p.Arg666Trp
LRG_461:g.23032C>T
NC_000019.9:g.45855814G>A
NM_000400.3:c.1996C>T

Protein change:

R666W

Links:

dbSNP: rs752510317

NCBI 1000 Genomes Browser:

rs752510317

Molecular consequence:

NM_000400.4:c.1996C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cerebrooculofacioskeletal syndrome 2 (COFS2)
Identifiers:: MONDO: MONDO:0012553; MedGen: C1853102; OMIM: 610756

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004194644	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 3, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005088764	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004194644

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 3, 2023)

unknown

clinical testing

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

SCV005088764

Breakthrough Genomics, Breakthrough Genomics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 28, 2022)

germline

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	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	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Baylor Genetics, SCV004194644.1

#	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

From Breakthrough Genomics, Breakthrough Genomics, SCV005088764.2

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

Description

This variant has been previously reported in patients with cerebro-oculo-facio-skeletal (COFS) syndrome as well as xeroderma pigmentosum and Cockayne syndrome crossover syndrome (XP/CS) in compound heterozygous state [PMID: 25716912, 18510925]. In vitro and in vivo functional studies revealed that XPD protein with the variant was completely defective in nucleotide excision repair (NER) of UV-induced DNA damage, lacking ATPase activity and helicase activity [PMID: 25716912, 18510924, 16135823].

#	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		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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