VCV000551809.13 - ClinVar

NM_000380.4(XPA):c.631C>T (p.Arg211Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

5 out of 6 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000380.4(XPA):c.631C>T (p.Arg211Ter)

Variation ID: 551809 Accession: VCV000551809.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q22.33 9: 97684965 (GRCh38) [ NCBI UCSC ] 9: 100447247 (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	Aug 5, 2018	Jun 29, 2025	Mar 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000380.4:c.631C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000371.1:p.Arg211Ter	nonsense
NM_001354975.2:c.505C>T	NP_001341904.1:p.Arg169Ter	nonsense
NR_027302.2:n.679C>T		non-coding transcript variant
NR_149091.2:n.407C>T		non-coding transcript variant
NR_149092.2:n.573C>T		non-coding transcript variant
NR_149093.2:n.679C>T		non-coding transcript variant
NR_149094.2:n.573C>T		non-coding transcript variant
NC_000009.12:g.97684965G>A
NC_000009.11:g.100447247G>A
NG_011642.1:g.17445C>T
LRG_471:g.17445C>T
LRG_471t1:c.631C>T	LRG_471p1:p.Arg211Ter

... more HGVS ... less HGVS

Protein change

R211*, R169*

Other names

Canonical SPDI

NC_000009.12:97684964:G:A

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA5148774 dbSNP: rs149226993 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.
XPA		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	405	495

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.
Xeroderma pigmentosum group A	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 20, 2024	RCV000666956.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 22, 2024	RCV001045901.9
Xeroderma pigmentosum	Pathogenic (1)	criteria provided, single submitter	Nov 29, 2018	RCV000781923.1

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.	Expand all rows Collapse all rows 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.
Pathogenic (Nov 29, 2018) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Xeroderma pigmentosum	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000920349.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (2) PubMed: 27607234‚ 1372103 Comment: show Variant summary: XPA c.631C>T (p.Arg211X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245906 control chromosomes (gnomAD). c.631C>T has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Xeroderma Pigmentosum (Satokata_1992, Zhou_2017). These data indicate that the variant is very likely to be associated with disease. A functional study indicates that the variant would "cause instability of the XPAC mRNA and loss of repair activity of the XPAC protein." (Satokata_1992) A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cties the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Apr 06, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV002584370.2 First in ClinVar: Oct 22, 2022 Last updated: Mar 04, 2023	Comment: show Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 63 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 1372103, 15214909, 31350202, 27607234) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Oct 30, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Xeroderma pigmentosum group A	Baylor Genetics Accession: SCV004206939.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Mar 20, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Xeroderma pigmentosum group A	Fulgent Genetics, Fulgent Genetics Accession: SCV005682080.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001209776.6 First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025	Publications: PubMed (5) PubMed: 1372103‚ 27607234‚ 8105686‚ 9671271‚ 24135642 Comment: show This sequence change creates a premature translational stop signal (p.Arg211) in the XPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the XPA protein. This variant is present in population databases (rs149226993, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with xeroderma pigmentosum (PMID: 1372103, 27607234). ClinVar contains an entry for this variant (Variation ID: 551809). This variant disrupts a region of the XPA protein in which other variant(s) (p.Arg228) have been determined to be pathogenic (PMID: 8105686, 9671271, 24135642, 27607234). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (May 09, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Xeroderma pigmentosum group A	Counsyl Accession: SCV000791333.2 First in ClinVar: Aug 05, 2018 Last updated: Jun 29, 2025	Publications: PubMed (4) PubMed: 1372103‚ 27607234‚ 9671271‚ 15214909 Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

Variant summary: XPA c.631C>T (p.Arg211X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245906 control chromosomes (gnomAD). c.631C>T has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Xeroderma Pigmentosum (Satokata_1992, Zhou_2017). These data indicate that the variant is very likely to be associated with disease. A functional study indicates that the variant would "cause instability of the XPAC mRNA and loss of repair activity of the XPAC protein." (Satokata_1992) A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cties the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 63 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 1372103, 15214909, 31350202, 27607234)

Comment:

This sequence change creates a premature translational stop signal (p.Arg211*) in the XPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the XPA protein. This variant is present in population databases (rs149226993, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with xeroderma pigmentosum (PMID: 1372103, 27607234). ClinVar contains an entry for this variant (Variation ID: 551809). This variant disrupts a region of the XPA protein in which other variant(s) (p.Arg228*) have been determined to be pathogenic (PMID: 8105686, 9671271, 24135642, 27607234). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and molecular epidemiological study of xeroderma pigmentosum in China: A case series of 19 patients.	Zhou EY	The Journal of dermatology	2017	PMID: 27607234
Mutational spectrum of Xeroderma pigmentosum group A in Egyptian patients.	Amr K	Gene	2014	PMID: 24135642
DNA-based prenatal diagnosis in a Chinese family with xeroderma pigmentosum group A.	Yang Y	The British journal of dermatology	2004	PMID: 15214909
Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein.	States JC	Human mutation	1998	PMID: 9671271
High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia.	Nishigori C	American journal of human genetics	1993	PMID: 8105686
Identification of splicing mutations of the last nucleotides of exons, a nonsense mutation, and a missense mutation of the XPAC gene as causes of group A xeroderma pigmentosum.	Satokata I	Mutation research	1992	PMID: 1372103

Text-mined citations for rs149226993 ...

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 Jun 29, 2025

ClinVar Genomic variation as it relates to human health

NM_000380.4(XPA):c.631C>T (p.Arg211Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs149226993 ...