ClinVar Genomic variation as it relates to human health
NM_005236.3(ERCC4):c.1727G>C (p.Arg576Thr)
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.
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(8); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005236.3(ERCC4):c.1727G>C (p.Arg576Thr)
Variation ID: 134158 Accession: VCV000134158.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.12 16: 13935659 (GRCh38) [ NCBI UCSC ] 16: 14029516 (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 May 1, 2024 Feb 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005236.3:c.1727G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005227.1:p.Arg576Thr missense NC_000016.10:g.13935659G>C NC_000016.9:g.14029516G>C NG_011442.1:g.20503G>C LRG_463:g.20503G>C LRG_463t1:c.1727G>C LRG_463p1:p.Arg576Thr Q92889:p.Arg576Thr - Protein change
- R576T
- Other names
- -
- Canonical SPDI
- NC_000016.10:13935658:G:C
-
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 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00054
The Genome Aggregation Database (gnomAD), exomes 0.00069
1000 Genomes Project 30x 0.00078
The Genome Aggregation Database (gnomAD) 0.00082
Trans-Omics for Precision Medicine (TOPMed) 0.00084
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00085
1000 Genomes Project 0.00100
- 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. |
|||
ERCC4 | - | - |
GRCh38 GRCh37 |
771 | 865 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, single submitter
|
Sep 9, 2021 | RCV000120831.6 | |
Likely benign (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV000651477.9 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001119237.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 4, 2022 | RCV002257433.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 17, 2022 | RCV001294105.3 | |
Uncertain significance (4) |
criteria provided, single submitter
|
Nov 3, 2021 | RCV001357601.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jul 16, 2021 | RCV002055332.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Nov 16, 2021 | RCV002515863.2 |
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
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum, group F
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001277596.1
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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Uncertain significance
(Sep 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group Q
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482918.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Uncertain significance
(Sep 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002071319.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.1727G>C, in exon 8 that results in an amino acid change, p.Arg576Thr. This sequence … (more)
DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.1727G>C, in exon 8 that results in an amino acid change, p.Arg576Thr. This sequence change has been described in the gnomAD database with a frequency of 0.13% in the Latino sub-population (dbSNP rs1800068). The p.Arg576Thr change has been reported in individuals with head and neck carcinoma and pancreatic cancer (PMIDs: 28678401, 28767289). The p.Arg576Thr change affects a moderately conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. The p.Arg576Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg576Thr change remains unknown at this time. (less)
|
|
Uncertain significance
(Jul 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
XFE progeroid syndrome
Fanconi anemia complementation group Q Xeroderma pigmentosum, group F
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002496110.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
Comment:
ERCC4 NM_005236.2 exon 8 p.Arg576Thr (c.1727G>C):This variant has been reported in the literature in at least 4 individuals: 1 with head/neck squamous cell carcinoma, 3 … (more)
ERCC4 NM_005236.2 exon 8 p.Arg576Thr (c.1727G>C):This variant has been reported in the literature in at least 4 individuals: 1 with head/neck squamous cell carcinoma, 3 with pancreatic ductal adenocarcinoma (Chanrasekharappa 2017 PMID:28678401, Shindo 2017 PMID:28767289). This variant is present in 0.1% (29/15276) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-13935659-G-C?dataset=gnomad_r3) This variant is present in ClinVar (Variation ID:134158). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
|
|
Uncertain significance
(Jan 04, 2022)
|
criteria provided, single submitter
Method: curation
|
Xeroderma pigmentosum
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537735.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ERCC4 c.1727G>C (p.R576T) variant has been reported in individuals with breast cancer, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, as well as healthy … (more)
The ERCC4 c.1727G>C (p.R576T) variant has been reported in individuals with breast cancer, pancreatic adenocarcinoma, head and neck squamous cell carcinoma, as well as healthy controls (PMID: 28767289, 28678401, 32008151, 24728327, doi 10.1200/PO.18.00090). It has been reported in a case-control study of breast cancer in 13/4807 cases and 16/4782 controls (PMID: 34117267). This variant was observed in 45/35426 chromosomes in the Latino subpopulation according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 134158). In silico tools are inconclusive, though one functional study suggests that the variant has reduced repair capacity in lymphoblastoid cell lines stressed with UV light (doi 10.1200/PO.18.00090). The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
|
|
|
Uncertain significance
(Aug 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group Q
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002032317.2
First in ClinVar: Dec 18, 2021 Last updated: Oct 22, 2022 |
Comment:
The ERCC4 c.1727G>C (p.Arg576Thr) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more)
The ERCC4 c.1727G>C (p.Arg576Thr) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer (PMID: 32008151, 34117267), head and neck squamous cell carcinoma (PMID: 28678401), and pancreatic ductal adenocarcinoma (PMID: 28767289). To our knowledge, this variant has not been reported in individuals with Fanconi anemia or Xeroderma pigmentosum. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
|
|
Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009706.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
Likely benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group Q
Xeroderma pigmentosum, group F Cockayne syndrome
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.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000773329.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
|
|
Uncertain significance
(Nov 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003685116.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1727G>C (p.R576T) alteration is located in exon 8 (coding exon 8) of the ERCC4 gene. This alteration results from a G to C substitution … (more)
The c.1727G>C (p.R576T) alteration is located in exon 8 (coding exon 8) of the ERCC4 gene. This alteration results from a G to C substitution at nucleotide position 1727, causing the arginine (R) at amino acid position 576 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742068.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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: SCV001972335.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
Uncertain significance
(-)
|
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: SCV001553115.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ERCC4 p.Arg576Thr variant was identified in 10 of 6374 proband chromosomes (frequency: 0.001569) from individuals with breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma or … (more)
The ERCC4 p.Arg576Thr variant was identified in 10 of 6374 proband chromosomes (frequency: 0.001569) from individuals with breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma or head and neck squamous cell carcinoma and was present in 2 of 154 control chromosomes (frequency: 0.01299) from healthy individuals (McVeigh_2020_PMID:32008151; West_2018; Shindo_2017_PMID:28767289; Chandrasekharappa_2017_PMID:28678401). The variant was identified in dbSNP (ID: rs1800068) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 185 of 281516 chromosomes at a frequency of 0.0006572 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: Latino in 45 of 35426 chromosomes (freq: 0.00127), European (non-Finnish) in 126 of 127888 chromosomes (freq: 0.000985), Other in 7 of 7216 chromosomes (freq: 0.00097), African in 5 of 24972 chromosomes (freq: 0.0002) and European (Finnish) in 2 of 25102 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Arg576 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional assays demonstrated defective DNA repair function after UV-induced DNA damage with ERCC4 p.R576T compared to wildtype (West_2018). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084996.1
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 |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study. | Li N | NPJ breast cancer | 2021 | PMID: 34117267 |
Diagnostic yield of a custom-designed multi-gene cancer panel in Irish patients with breast cancer. | McVeigh ÚM | Irish journal of medical science | 2020 | PMID: 32008151 |
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. | Shindo K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28767289 |
Assessing the spectrum of germline variation in Fanconi anemia genes among patients with head and neck carcinoma before age 50. | Chandrasekharappa SC | Cancer | 2017 | PMID: 28678401 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Text-mined citations for rs1800068 ...
HelpRecord last updated Sep 29, 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.