Variant summary: XPC c.1496C>T (p.Ala499Val) 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 0.24 in 276928 control chromosomes in the gnomAD database, including 8807 homozygotes. The observed variant frequency is approximately 171-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.0014), strongly suggesting that the variant is benign. The variant has been indicated to be associated with an increased risk of cancer (He_2013). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
ClinVar Genomic variation as it relates to human health
NM_004628.5(XPC):c.1496C>T (p.Ala499Val)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004628.5(XPC):c.1496C>T (p.Ala499Val)
Variation ID: 135485 Accession: VCV000135485.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.1 3: 14158387 (GRCh38) [ NCBI UCSC ] 3: 14199887 (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 Sep 29, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004628.5:c.1496C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004619.3:p.Ala499Val missense NM_001354726.2:c.917C>T NP_001341655.1:p.Ala306Val missense NM_001354727.2:c.1496C>T NP_001341656.1:p.Ala499Val missense NM_001354729.2:c.1478C>T NP_001341658.1:p.Ala493Val missense NM_001354730.2:c.1496C>T NP_001341659.1:p.Ala499Val missense NR_148950.2:n.1529C>T non-coding transcript variant NR_148951.2:n.1405C>T non-coding transcript variant NC_000003.12:g.14158387G>A NC_000003.11:g.14199887G>A NG_011763.1:g.25286C>T LRG_472:g.25286C>T LRG_472t1:c.1496C>T LRG_472p1:p.Ala499Val Q01831:p.Ala499Val - Protein change
- A499V, A306V, A493V
- Other names
- -
- Canonical SPDI
- NC_000003.12:14158386: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.
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0.23303 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.20058
Trans-Omics for Precision Medicine (TOPMed) 0.20177
The Genome Aggregation Database (gnomAD) 0.21224
1000 Genomes Project 30x 0.22923
1000 Genomes Project 0.23303
Exome Aggregation Consortium (ExAC) 0.23775
The Genome Aggregation Database (gnomAD), exomes 0.24352
- 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. |
|||
| XPC | - | - |
GRCh38 GRCh37 |
989 | 1098 | |
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. |
|---|---|---|---|---|
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 27, 2018 | RCV000122343.7 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2021 | RCV000325908.6 | |
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV001510258.9 | |
| Benign (1) |
criteria provided, single submitter
|
Jul 7, 2023 | RCV003315793.1 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Aug 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920353.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: XPC c.1496C>T (p.Ala499Val) 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.1496C>T (p.Ala499Val) 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 0.24 in 276928 control chromosomes in the gnomAD database, including 8807 homozygotes. The observed variant frequency is approximately 171-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.0014), strongly suggesting that the variant is benign. The variant has been indicated to be associated with an increased risk of cancer (He_2013). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
|
Benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum, group C
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000441375.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
|
Benign
(Feb 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001882862.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 26001739, 23436679, 27153395, 15700316, 20369554, 20193233, 24728327, 23400628, 17575242, 21113018, 19706757, 17882560)
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001717248.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024 |
|
|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000310535.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
Benign
(Dec 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum, group C
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002514009.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
|
|
|
Benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum group A
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004016283.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
|
Benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005241622.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000086573.1
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
|
Comment:
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
This variant is associated with the following publications: (PMID: 26001739, 23436679, 27153395, 15700316, 20369554, 20193233, 24728327, 23400628, 17575242, 21113018, 19706757, 17882560)
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:
Variant summary: XPC c.1496C>T (p.Ala499Val) 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 0.24 in 276928 control chromosomes in the gnomAD database, including 8807 homozygotes. The observed variant frequency is approximately 171-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.0014), strongly suggesting that the variant is benign. The variant has been indicated to be associated with an increased risk of cancer (He_2013). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
This variant is associated with the following publications: (PMID: 26001739, 23436679, 27153395, 15700316, 20369554, 20193233, 24728327, 23400628, 17575242, 21113018, 19706757, 17882560)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Associations of Lys939Gln and Ala499Val polymorphisms of the XPC gene with cancer susceptibility: a meta-analysis. | He J | International journal of cancer | 2013 | PMID: 23400628 |
Text-mined citations for rs2228000 ...
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 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.