ClinVar Genomic variation as it relates to human health
NM_004628.5(XPC):c.1001C>A (p.Pro334His)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004628.5(XPC):c.1001C>A (p.Pro334His)
Variation ID: 253 Accession: VCV000000253.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 14158882 (GRCh38) [ NCBI UCSC ] 3: 14200382 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004628.5:c.1001C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004619.3:p.Pro334His missense NM_001354726.2:c.422C>A NP_001341655.1:p.Pro141His missense NM_001354727.2:c.1001C>A NP_001341656.1:p.Pro334His missense NM_001354729.2:c.983C>A NP_001341658.1:p.Pro328His missense NM_001354730.2:c.1001C>A NP_001341659.1:p.Pro334His missense NR_148950.2:n.1034C>A non-coding transcript variant NR_148951.2:n.910C>A non-coding transcript variant NC_000003.12:g.14158882G>T NC_000003.11:g.14200382G>T NG_011763.1:g.24791C>A LRG_472:g.24791C>A LRG_472t1:c.1001C>A LRG_472p1:p.Pro334His Q01831:p.Pro334His - Protein change
- P334H, P141H, P328H
- Other names
- P218H
- Canonical SPDI
- NC_000003.12:14158881:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00559 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00559
1000 Genomes Project 30x 0.00640
The Genome Aggregation Database (gnomAD) 0.00806
Trans-Omics for Precision Medicine (TOPMed) 0.00861
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 | ||
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HI score
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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. |
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XPC | - | - |
GRCh38 GRCh37 |
964 | 1072 |
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. |
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Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV000000277.10 | |
Benign (2) |
criteria provided, single submitter
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Feb 18, 2022 | RCV000122346.3 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000885048.15 | |
Benign (1) |
criteria provided, single submitter
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Mar 26, 2020 | RCV002257356.1 | |
Benign (1) |
criteria provided, single submitter
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Apr 10, 2021 | RCV003904788.1 |
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. |
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Benign
(Dec 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001835975.1
First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18955168, 8298653, 25333069, 17079196, 29973595, 30516811, 30675318, 31816862, 24728327, 18809580, 30256826, 27153395) (less)
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001028471.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Benign
(Apr 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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XPC-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004720634.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 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).
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum, group C
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001307224.1
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Feb 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363337.2
First in ClinVar: Jun 22, 2020 Last updated: Mar 12, 2022 |
Comment:
Variant summary: XPC c.1001C>A (p.Pro334His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: XPC c.1001C>A (p.Pro334His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 247062 control chromosomes, predominantly at a frequency of 0.025 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1001C>A has been reported in the literature (example, Bonache_2018, Li_1993, Martin-Morales_2018, Maxwell_2016, Pugh_2019, Ramirez-Calvo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, BernardesdeJesus_2008, Bidon_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Mar 26, 2020)
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criteria provided, single submitter
Method: curation
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Xeroderma pigmentosum
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002537469.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum, group C
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV001136327.2
First in ClinVar: Jan 13, 2020 Last updated: Aug 25, 2023 |
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Benign
(Feb 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004149240.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
XPC: BP4, BS1, BS2
Number of individuals with the variant: 3
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Pathogenic
(Dec 01, 1993)
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no assertion criteria provided
Method: literature only
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XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP C
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020421.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In XPC (278720) cell line XP1MI, Li et al. (1993) identified a mutation in the XPC gene, resulting in a pro218-to-his (P218H) substitution. The finding … (more)
In XPC (278720) cell line XP1MI, Li et al. (1993) identified a mutation in the XPC gene, resulting in a pro218-to-his (P218H) substitution. The finding suggested that the cell line was either homozygous or hemizygous for this mutation. The XP1MI cell line was the most UV-sensitive of 5 cell lines analyzed by Li et al. (1993). Furthermore, the patient demonstrated XP-associated neurologic abnormalities, a rarity in group C. (less)
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Uncertain significance
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Xeroderma pigmentosum, group C
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142327.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_004628.4:c.1001C>A (p.Pro334His) was previously reported as P218H. This variant has an allele frequency of 0.026 in African subpopulation in the gnomAD database. It has been … (more)
NM_004628.4:c.1001C>A (p.Pro334His) was previously reported as P218H. This variant has an allele frequency of 0.026 in African subpopulation in the gnomAD database. It has been reported previously in individuals with Xeroderma Pigmentosum in homozygous state (PMID: 17079196, 17084680). Functional studies show p.Pro334His mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1 (PMID: 18809580). Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT vs 1 pathogenic prediction from DANN and the position is not conserved. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, BP4, BP1, PS3, PM3_Supporting. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000086576.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
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
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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 |
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Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS). | Ramírez-Calvo M | Hereditary cancer in clinical practice | 2019 | PMID: 30675318 |
Use of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Population. | Pugh J | JAMA dermatology | 2019 | PMID: 30516811 |
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition. | Martin-Morales L | PloS one | 2018 | PMID: 30256826 |
XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1. | Bidon B | Nature communications | 2018 | PMID: 29973595 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Dissection of the molecular defects caused by pathogenic mutations in the DNA repair factor XPC. | Bernardes de Jesus BM | Molecular and cellular biology | 2008 | PMID: 18809580 |
Characterization of molecular defects in xeroderma pigmentosum group C. | Li L | Nature genetics | 1993 | PMID: 8298653 |
Text-mined citations for rs74737358 ...
HelpRecord last updated Apr 15, 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.