VCV003241411.2 - ClinVar

NM_000400.4(ERCC2):c.1532G>A (p.Arg511Gln)

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.

(2)

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.

Pathogenic/Likely pathogenic

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.1532G>A (p.Arg511Gln)

Variation ID: 3241411 Accession: VCV003241411.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.32 19: 45355676 (GRCh38) [ NCBI UCSC ] 19: 45858934 (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 17, 2024	Jul 15, 2024	Apr 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000400.4:c.1532G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000391.1:p.Arg511Gln	missense
NC_000019.10:g.45355676C>T
NC_000019.9:g.45858934C>T
NG_007067.2:g.19912G>A
LRG_461:g.19912G>A
LRG_461t1:c.1532G>A	LRG_461p1:p.Arg511Gln

... more HGVS ... less HGVS

Protein change

R511Q

Other names

Canonical SPDI

NC_000019.10:45355675:C:T

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.

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

Links

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.
Cerebrooculofacioskeletal syndrome 2	Likely pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV004576392.1
Xeroderma pigmentosum	Pathogenic (1)	criteria provided, single submitter	Apr 18, 2024	RCV004587649.1

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.
Likely pathogenic (Jan 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cerebrooculofacioskeletal syndrome 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005060334.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Apr 18, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Xeroderma pigmentosum Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005077251.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (4) PubMed: 26884178‚ 11156600‚ 19179371‚ 31110295 Comment: Variant summary: ERCC2 c.1532G>A (p.Arg511Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: ERCC2 c.1532G>A (p.Arg511Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251470 control chromosomes. c.1532G>A has been reported as biallelic genotypes in the literature in multiple individuals affected with Xeroderma Pigmentosum (example, Lehmann_2001, Fassihi_2016, Limisirichaikul_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Limisirichaikul_2009). The most pronounced variant effect results in 40% of normal unscheduled DNA synthesis (UDS) activity as a measure of nucleotide excision repair (NER). The following publications have been ascertained in the context of this evaluation (PMID: 31110295, 26884178, 11156600, 19179371). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Comment:

Variant summary: ERCC2 c.1532G>A (p.Arg511Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251470 control chromosomes. c.1532G>A has been reported as biallelic genotypes in the literature in multiple individuals affected with Xeroderma Pigmentosum (example, Lehmann_2001, Fassihi_2016, Limisirichaikul_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Limisirichaikul_2009). The most pronounced variant effect results in 40% of normal unscheduled DNA synthesis (UDS) activity as a measure of nucleotide excision repair (NER). The following publications have been ascertained in the context of this evaluation (PMID: 31110295, 26884178, 11156600, 19179371). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Title	Author	Journal	Year	Link
Transcription preinitiation complex structure and dynamics provide insight into genetic diseases.	Yan C	Nature structural & molecular biology	2019	PMID: 31110295
Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.	Fassihi H	Proceedings of the National Academy of Sciences of the United States of America	2016	PMID: 26884178
A rapid non-radioactive technique for measurement of repair synthesis in primary human fibroblasts by incorporation of ethynyl deoxyuridine (EdU).	Limsirichaikul S	Nucleic acids research	2009	PMID: 19179371
The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases.	Lehmann AR	Genes & development	2001	PMID: 11156600

Text-mined citations for this variant ...

Record last updated Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000400.4(ERCC2):c.1532G>A (p.Arg511Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...