ClinVar Genomic variation as it relates to human health
NM_000380.4(XPA):c.619C>T (p.Arg207Ter)
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_000380.4(XPA):c.619C>T (p.Arg207Ter)
Variation ID: 996 Accession: VCV000000996.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.33 9: 97684977 (GRCh38) [ NCBI UCSC ] 9: 100447259 (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 May 1, 2024 Mar 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000380.4:c.619C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000371.1:p.Arg207Ter nonsense NM_001354975.2:c.493C>T NP_001341904.1:p.Arg165Ter nonsense NR_027302.2:n.667C>T non-coding transcript variant NR_149091.2:n.395C>T non-coding transcript variant NR_149092.2:n.561C>T non-coding transcript variant NR_149093.2:n.667C>T non-coding transcript variant NR_149094.2:n.561C>T non-coding transcript variant NC_000009.12:g.97684977G>A NC_000009.11:g.100447259G>A NG_011642.1:g.17433C>T LRG_471:g.17433C>T LRG_471t1:c.619C>T LRG_471p1:p.Arg207Ter - Protein change
- R207*, R165*
- Other names
- NP_000371.1:p.Arg207X
- Canonical SPDI
- NC_000009.12:97684976:G:A
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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XPA | - | - |
GRCh38 GRCh37 |
358 | 406 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2024 | RCV000001051.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000657642.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 9, 2021 | RCV001420782.1 |
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
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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
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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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Pathogenic
(May 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623142.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: XPA c.619C>T (p.Arg207X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: XPA c.619C>T (p.Arg207X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251098 control chromosomes. c.619C>T has been reported in the literature in multiple individuals affected with Xeroderma Pigmentosum (example, Satokata_1992, Messaoud_2012, Zhang_2017, Salomao_2018). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum group A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000795241.1
First in ClinVar: Sep 02, 2017 Last updated: Sep 02, 2017 |
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Pathogenic
(May 18, 2018)
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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: SCV000779387.2
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
Comment:
The R207X pathogenic variant in the XPA gene has been reported previously either in the homozygous state or in combination with another XPA variant in … (more)
The R207X pathogenic variant in the XPA gene has been reported previously either in the homozygous state or in combination with another XPA variant in multiple individuals with xeroderma pigmentosum (Satokata et al., 1992; Messaoud et al., 2012; Santiago et al., 2015; Zhang et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies demonstrated that R207X is associated with impaired function of the XPA protein as a processivity factor (Bartels et al., 2007). The R207X variant is observed in 6/245,910 (0.0002%) alleles in large population cohorts (Lek et al., 2016). We interpret R207X as a pathogenic variant. (less)
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Pathogenic
(Dec 01, 2015)
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criteria provided, single submitter
Method: research
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Xeroderma pigmentosum group A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Medical Molecular Genetics Department, National Research Center
Accession: SCV001335297.1
First in ClinVar: Jun 15, 2020 Last updated: Jun 15, 2020 |
Number of individuals with the variant: 4
Family history: yes
Sex: mixed
Geographic origin: North Africa/Egypt
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Pathogenic
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001480097.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Clinical Features:
Cerebellar ataxia (present)
Sex: female
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Pathogenic
(Dec 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum group A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002776876.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum group A
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841376.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000996 / PMID: 1372102). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present) , Delayed speech and language development (present)
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Pathogenic
(May 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum group A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004206955.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 28, 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: SCV002242897.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg207*) in the XPA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg207*) in the XPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XPA are known to be pathogenic (PMID: 27607234). This variant is present in population databases (rs104894133, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 1372102, 9671271). ClinVar contains an entry for this variant (Variation ID: 996). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Xeroderma pigmentosum, group A
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005016544.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
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Pathogenic
(Mar 01, 1992)
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no assertion criteria provided
Method: literature only
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XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021201.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a Palestinian patient with severe XPA (278700), Satokata et al. (1992) identified homozygosity for a nucleotide transition in the XPA gene, resulting in an … (more)
In a Palestinian patient with severe XPA (278700), Satokata et al. (1992) identified homozygosity for a nucleotide transition in the XPA gene, resulting in an arg207-to-ter (R207X) substitution. (less)
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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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Neurological manifestations of xeroderma pigmentosum due to XPA gene mutation. | Salomão RPA | Practical neurology | 2018 | PMID: 30077970 |
Expansion of the genotypic and phenotypic spectrum of xeroderma pigmentosum in Chinese population. | Zhang J | Photodermatology, photoimmunology & photomedicine | 2017 | PMID: 27982466 |
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 |
Severe phenotypes in two Tunisian families with novel XPA mutations: evidence for a correlation between mutation location and disease severity. | Messaoud O | Archives of dermatological research | 2012 | PMID: 22081045 |
Recognition of helical kinks by xeroderma pigmentosum group A protein triggers DNA excision repair. | Camenisch U | Nature structural & molecular biology | 2006 | PMID: 16491090 |
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 |
Three nonsense mutations responsible for group A xeroderma pigmentosum. | Satokata I | Mutation research | 1992 | PMID: 1372102 |
Text-mined citations for rs104894133 ...
HelpRecord last updated May 01, 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.