VCV000001718.18 - ClinVar

NM_000082.4(ERCC8):c.613G>C (p.Ala205Pro)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (2); Likely pathogenic (1)

3 out of 6 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000082.4(ERCC8):c.613G>C (p.Ala205Pro)

Variation ID: 1718 Accession: VCV000001718.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q12.1 5: 60902446 (GRCh38) [ NCBI UCSC ] 5: 60198273 (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 23, 2013	Sep 5, 2026	Aug 26, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000082.4:c.613G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000073.1:p.Ala205Pro	missense
NM_001007233.3:c.439G>C	NP_001007234.1:p.Ala147Pro	missense
NM_001290285.2:c.154G>C	NP_001277214.1:p.Ala52Pro	missense
NC_000005.10:g.60902446C>G
NC_000005.9:g.60198273C>G
NG_009289.1:g.47633G>C
LRG_466:g.47633G>C
LRG_466t1:c.613G>C	LRG_466p1:p.Ala205Pro
	Q13216:p.Ala205Pro

... more HGVS ... less HGVS

Protein change

A205P, A147P, A52P

Other names

Canonical SPDI

NC_000005.10:60902445:C:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00006

Links

dbSNP: rs121434326 ClinGen: CA219858 UniProtKB: Q13216#VAR_025381 UniProtKB/Swiss-Prot: VAR_025381 OMIM: 609412.0005 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.
ERCC8		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	576	702

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.
Cockayne syndrome type 1	Conflicting classifications of pathogenicity (2)	no assertion criteria provided	May 12, 2017	RCV000001788.6
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 26, 2026	RCV000059650.16
Cockayne syndrome type 1 UV-sensitive syndrome 2	Likely pathogenic (1)	criteria provided, single submitter	Jun 24, 2024	RCV005031380.1

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.	Expand all rows Collapse all rows 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 (Jun 24, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cockayne syndrome type 1 UV-sensitive syndrome 2 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV005673544.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 07, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001588880.7 First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 14661080‚ 16949367‚ 29531219‚ 32048102 Comment: show This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 205 of the ERCC8 protein (p.Ala205Pro). This variant is present in population databases (rs121434326, gnomAD 0.05%). This missense change has been observed in individual(s) with Cockayne syndrome (PMID: 14661080, 32048102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1718). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ERCC8 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ERCC8 function (PMID: 16949367, 29531219). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 26, 2026) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001820441.6 First in ClinVar: Sep 08, 2021 Last updated: Sep 05, 2026	Comment: show Published functional studies demonstrate a damaging effect (PMID: 29531219); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 40225944, 19894250, 32048102, 29531219, 37751047, 16949367, 14661080, 28333167, 16865293, 17084038, 25653723, 23571135, Guo2024_Paper) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 01, 2004) N Not contributing to aggregate classification	no assertion criteria provided	COCKAYNE SYNDROME A	OMIM Accession: SCV000021944.3 First in ClinVar: Apr 04, 2013 Last updated: Feb 01, 2022	Publications: PubMed (1) PubMed: 14661080 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a cell line from a patient with Cockayne syndrome A (216400), Cao et al. (2004) identified compound heterozygosity for 2 mutations in the ERCC8 … (more) In a cell line from a patient with Cockayne syndrome A (216400), Cao et al. (2004) identified compound heterozygosity for 2 mutations in the ERCC8 gene: a 649G-C transversion, resulting in an ala205-to-pro (A205P) substitution, and E13X (609412.0003). (less)

Uncertain significance (May 12, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Cockayne syndrome type 1	Counsyl Accession: SCV000800534.2 First in ClinVar: Oct 11, 2015 Last updated: Jun 29, 2025	Publications: PubMed (1) PubMed: 14661080 Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

not provided (-) N Not contributing to aggregate classification	no classification provided	not provided	UniProtKB/Swiss-Prot Accession: SCV000091220.1 First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013	Observation: 1 Collection method: not provided Allele origin: not provided Affected status: not provided Observation 1 Collection method: not provided Allele origin: not provided Affected status: not provided

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 205 of the ERCC8 protein (p.Ala205Pro). This variant is present in population databases (rs121434326, gnomAD 0.05%). This missense change has been observed in individual(s) with Cockayne syndrome (PMID: 14661080, 32048102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1718). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ERCC8 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ERCC8 function (PMID: 16949367, 29531219). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate a damaging effect (PMID: 29531219); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 40225944, 19894250, 32048102, 29531219, 37751047, 16949367, 14661080, 28333167, 16865293, 17084038, 25653723, 23571135, Guo2024_Paper)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Multimodal imaging in a family with Cockayne syndrome with a novel pathogenic mutation in the ERCC8 gene, and significant phenotypic variability.	Cho S	Documenta ophthalmologica. Advances in ophthalmology	2020	PMID: 32048102
TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A.	Pines A	Nature communications	2018	PMID: 29531219
A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1.	Jin J	Molecular cell	2006	PMID: 16949367
CKN1 (MIM 216400): mutations in Cockayne syndrome type A and a new common polymorphism.	Cao H	Journal of human genetics	2004	PMID: 14661080

Text-mined citations for rs121434326 ...

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 05, 2026