This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ClinVar Genomic variation as it relates to human health
NM_000122.2(ERCC3):c.2111C>T (p.Ser704Leu)
Germline
Classification
Help
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.
(11)
Help
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.
Benign/Likely benign
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000122.2(ERCC3):c.2111C>T (p.Ser704Leu)
Variation ID: 134120 Accession: VCV000134120.47
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q14.3 2: 127259402 (GRCh38) [ NCBI UCSC ] 2: 128016978 (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 Oct 20, 2024 Jan 28, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000122.2:c.2111C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000113.1:p.Ser704Leu missense NM_001303416.2:c.1919C>T NP_001290345.1:p.Ser640Leu missense NM_001303418.2:c.1919C>T NP_001290347.1:p.Ser640Leu missense NC_000002.12:g.127259402G>A NC_000002.11:g.128016978G>A NG_007454.1:g.39775C>T LRG_462:g.39775C>T LRG_462t1:c.2111C>T LRG_462p1:p.Ser704Leu P19447:p.Ser704Leu - Protein change
- S704L, S640L
- Other names
- -
- Canonical SPDI
- NC_000002.12:127259401:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00100 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00175
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00192
Exome Aggregation Consortium (ExAC) 0.00217
The Genome Aggregation Database (gnomAD), exomes 0.00220
The Genome Aggregation Database (gnomAD) 0.00227
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ERCC3 | - | - |
GRCh38 GRCh37 |
563 | 593 | |
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 provided (1) |
no classification provided
|
Sep 19, 2013 | RCV000120792.2 | |
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
May 28, 2019 | RCV000986805.6 | |
| Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2024 | RCV000861013.34 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 12, 2022 | RCV002257424.2 | |
|
ERCC3-related disorder
|
Benign (1) |
no assertion criteria provided
|
Feb 25, 2020 | RCV003925182.2 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001001212.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum group B
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135938.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum group B
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001292700.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Jan 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001814079.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
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: 28259476, … (more)
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: 28259476, 27153395, 31346352, 30256826, 16550608, 30414346, 16574953, 24728327) (less)
|
|
|
Likely benign
(Jan 12, 2022)
|
criteria provided, single submitter
Method: curation
|
Xeroderma pigmentosum
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532619.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Likely benign
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001152396.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
ERCC3: BS2
Number of individuals with the variant: 3
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809766.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549770.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ERCC3 p.Ser640Leu variant was not identified in the literature but was identified in dbSNP (ID: rs4150521) and ClinVar (classified as benign by Invitae; likely … (more)
The ERCC3 p.Ser640Leu variant was not identified in the literature but was identified in dbSNP (ID: rs4150521) and ClinVar (classified as benign by Invitae; likely benign by Mendelics for Xeroderma pigmentosum, complementation group b and uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 607 of 268178 chromosomes (2 homozygous) at a frequency of 0.002263 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 182 of 25100 chromosomes (freq: 0.007251), Other in 32 of 6702 chromosomes (freq: 0.004775), Latino in 103 of 35102 chromosomes (freq: 0.002934), European (non-Finnish) in 257 of 118038 chromosomes (freq: 0.002177), Ashkenazi Jewish in 12 of 9854 chromosomes (freq: 0.001218), African in 12 of 23604 chromosomes (freq: 0.000508) and South Asian in 9 of 30526 chromosomes (freq: 0.000295), but was not observed in the East Asian population. The p.Ser640 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967009.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Benign
(Feb 25, 2020)
|
no assertion criteria provided
Method: clinical testing
|
ERCC3-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004739484.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084956.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
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
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
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: 28259476, 27153395, 31346352, 30256826, 16550608, 30414346, 16574953, 24728327)
Comment:
ERCC3: BS2
Comment:
The ERCC3 p.Ser640Leu variant was not identified in the literature but was identified in dbSNP (ID: rs4150521) and ClinVar (classified as benign by Invitae; likely benign by Mendelics for Xeroderma pigmentosum, complementation group b and uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 607 of 268178 chromosomes (2 homozygous) at a frequency of 0.002263 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 182 of 25100 chromosomes (freq: 0.007251), Other in 32 of 6702 chromosomes (freq: 0.004775), Latino in 103 of 35102 chromosomes (freq: 0.002934), European (non-Finnish) in 257 of 118038 chromosomes (freq: 0.002177), Ashkenazi Jewish in 12 of 9854 chromosomes (freq: 0.001218), African in 12 of 23604 chromosomes (freq: 0.000508) and South Asian in 9 of 30526 chromosomes (freq: 0.000295), but was not observed in the East Asian population. The p.Ser640 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
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: 28259476, 27153395, 31346352, 30256826, 16550608, 30414346, 16574953, 24728327)
Comment:
ERCC3: BS2
Comment:
The ERCC3 p.Ser640Leu variant was not identified in the literature but was identified in dbSNP (ID: rs4150521) and ClinVar (classified as benign by Invitae; likely benign by Mendelics for Xeroderma pigmentosum, complementation group b and uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 607 of 268178 chromosomes (2 homozygous) at a frequency of 0.002263 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 182 of 25100 chromosomes (freq: 0.007251), Other in 32 of 6702 chromosomes (freq: 0.004775), Latino in 103 of 35102 chromosomes (freq: 0.002934), European (non-Finnish) in 257 of 118038 chromosomes (freq: 0.002177), Ashkenazi Jewish in 12 of 9854 chromosomes (freq: 0.001218), African in 12 of 23604 chromosomes (freq: 0.000508) and South Asian in 9 of 30526 chromosomes (freq: 0.000295), but was not observed in the East Asian population. The p.Ser640 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| 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 rs4150521 ...
HelpThese 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 Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.