VCV000134099.14 - ClinVar

NM_000400.4(ERCC2):c.1887G>C (p.Gln629His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000400.4(ERCC2):c.1887G>C (p.Gln629His)

Variation ID: 134099 Accession: VCV000134099.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.32 19: 45352761 (GRCh38) [ NCBI UCSC ] 19: 45856019 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 9, 2014	Feb 14, 2024	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000400.4:c.1887G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000391.1:p.Gln629His	missense
NC_000019.10:g.45352761C>G
NC_000019.9:g.45856019C>G
NG_007067.2:g.22827G>C
LRG_461:g.22827G>C
LRG_461t1:c.1887G>C	LRG_461p1:p.Gln629His

... more HGVS ... less HGVS

Protein change

Q629H

Other names

Canonical SPDI

NC_000019.10:45352760:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00010

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00078

Links

ClinGen: CA158764 dbSNP: rs200665173 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ERCC2		-	-	GRCh38 GRCh37	2131	2185

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000120771.1
Cerebrooculofacioskeletal syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Mar 5, 2018	RCV000662069.4
Cerebrooculofacioskeletal syndrome 2 Trichothiodystrophy 1, photosensitive Xeroderma pigmentosum, group D	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2022	RCV000764209.3
Trichothiodystrophy 1, photosensitive	Uncertain significance (1)	criteria provided, single submitter	Mar 5, 2018	RCV000662070.4
Xeroderma pigmentosum, group D	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 5, 2018	RCV000662071.8
Cerebrooculofacioskeletal syndrome 2	Uncertain significance (1)	criteria provided, single submitter	Jul 17, 2019	RCV001329853.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 22, 2024	RCV001854613.4
Xeroderma pigmentosum	Uncertain significance (1)	criteria provided, single submitter	Nov 16, 2021	RCV002256052.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebrooculofacioskeletal syndrome 1 Affected status: no Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784405.2 First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 20-29 years Sex: female Geographic origin: Iran
Uncertain significance (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Trichothiodystrophy 1, photosensitive Affected status: no Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784406.2 First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 20-29 years Sex: female Geographic origin: Iran
Uncertain significance (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Xeroderma pigmentosum, group D Affected status: no Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784407.2 First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 20-29 years Sex: female Geographic origin: Iran
Uncertain significance (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002122791.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Comment: This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 629 of the ERCC2 protein (p.Gln629His). … (more) This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 629 of the ERCC2 protein (p.Gln629His). This variant is present in population databases (rs200665173, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134099). 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 ERCC2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jul 17, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebrooculofacioskeletal syndrome 2 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001521402.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Nov 16, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Xeroderma pigmentosum Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002531580.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The ERCC2 c.1887G>C (p.Q629H) variant has not been reported in the literature to our knowledge. It was observed in 9/30614 chromosomes of the South Asian … (more) The ERCC2 c.1887G>C (p.Q629H) variant has not been reported in the literature to our knowledge. It was observed in 9/30614 chromosomes of the South Asian subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
Uncertain significance (Apr 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Xeroderma pigmentosum, group D Trichothiodystrophy 1, photosensitive Cerebrooculofacioskeletal syndrome 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895212.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jan 15, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Xeroderma pigmentosum, group D Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001288499.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084935.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 629 of the ERCC2 protein (p.Gln629His). This variant is present in population databases (rs200665173, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134099). 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 ERCC2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs200665173 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000400.4(ERCC2):c.1887G>C (p.Gln629His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200665173 ...