VCV000190215.28 - ClinVar

NM_004628.5(XPC):c.2815C>A (p.Gln939Lys)

Germline

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.

(11)

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

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.2815C>A (p.Gln939Lys)

Variation ID: 190215 Accession: VCV000190215.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.1 3: 14145949 (GRCh38) [ NCBI UCSC ] 3: 14187449 (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	May 9, 2015	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004628.5:c.2815C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004619.3:p.Gln939Lys	missense
NM_001354726.2:c.2236C>A	NP_001341655.1:p.Gln746Lys	missense
NM_001354727.2:c.2809C>A	NP_001341656.1:p.Gln937Lys	missense
NM_001354729.2:c.2797C>A	NP_001341658.1:p.Gln933Lys	missense
NM_001354730.2:c.2569C>A	NP_001341659.1:p.Gln857Lys	missense
NR_148950.2:n.2687C>A		non-coding transcript variant
NR_148951.2:n.2563C>A		non-coding transcript variant
NC_000003.12:g.14145949G>T
NC_000003.11:g.14187449G>T
NG_011763.1:g.37724C>A
LRG_472:g.37724C>A
LRG_472t1:c.2815C>A	LRG_472p1:p.Gln939Lys
	Q01831:p.Gln939Lys

... more HGVS ... less HGVS

Protein change

Q939K, Q857K, Q933K, Q937K, Q746K

Other names

Canonical SPDI

NC_000003.12:14145948:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

0.31530 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.63254

The Genome Aggregation Database (gnomAD), exomes 0.63346

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.64206

Trans-Omics for Precision Medicine (TOPMed) 0.64883

The Genome Aggregation Database (gnomAD) 0.64910

1000 Genomes Project 0.68470

1000 Genomes Project 30x 0.68848

Links

PharmGKB Clinical Annotation: 655386612 ClinGen: CA199619 UniProtKB: Q01831#VAR_005848 dbSNP: rs2228001 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.
TMEM43		No evidence available	No evidence available	GRCh38 GRCh37	952	996
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.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Aug 27, 2018	RCV000170436.15
Arrhythmogenic right ventricular cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000331098.13
Xeroderma pigmentosum	Benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000380504.13
Xeroderma pigmentosum, group C	Benign (2)	criteria provided, multiple submitters, no conflicts	Dec 5, 2021	RCV001150524.13
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001513521.27

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 (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000920354.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (1) PubMed: 23400628 Comment: Variant summary: XPC c.2815C>A (p.Gln939Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more) Variant summary: XPC c.2815C>A (p.Gln939Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.64 in 275306 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 450-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 found to have a slightly associated increased risk for cancer (He_2013) however the relevance of this finding to an inherited cause of Xeroderma Pigmentosum is not unlikely. A ClinVar submisson from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001721148.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (Jun 20, 2012)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Not specified (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Claritas Genomics Accession: SCV000222873.1 First in ClinVar: May 09, 2015 Last updated: May 09, 2015
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310542.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Xeroderma Pigmentosum Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000441362.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Cardiomyopathy, ARVC Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000484037.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Xeroderma pigmentosum, group C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001311597.1 First in ClinVar: May 31, 2020 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 (Dec 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Xeroderma pigmentosum, group C Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002513992.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Benign (Jul 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004149230.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: XPC: BP4, BS1, BS2 Number of individuals with the variant: 1
Benign (Jan 10, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001950548.2 First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 20056640, 23819639, 20658464, 23400628, 15700316, 19027756, 23269608, 20193233, 14729591, 27153395)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005264614.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
click to load more click to collapse

Comment:

Variant summary: XPC c.2815C>A (p.Gln939Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.64 in 275306 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 450-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 found to have a slightly associated increased risk for cancer (He_2013) however the relevance of this finding to an inherited cause of Xeroderma Pigmentosum is not unlikely. A ClinVar submisson from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely 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.

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:

Citations for germline classification of this variant

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 rs2228001 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004628.5(XPC):c.2815C>A (p.Gln939Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2228001 ...