VCV001342722.2 - ClinVar

NM_004628.5(XPC):c.2250+1G>A

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004628.5(XPC):c.2250+1G>A

Variation ID: 1342722 Accession: VCV001342722.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.1 3: 14148813 (GRCh38) [ NCBI UCSC ] 3: 14190313 (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	Sep 3, 2022	Apr 20, 2024	Mar 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_004628.5:c.2250+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001354726.2:c.1671+1G>A		splice donor
NM_001354727.2:c.2244+1G>A		splice donor
NM_001354729.2:c.2232+1G>A		splice donor
NM_001354730.2:c.2004+1G>A		splice donor
NC_000003.12:g.14148813C>T
NC_000003.11:g.14190313C>T
NG_011763.1:g.34860G>A
NG_098743.1:g.361C>T
LRG_472:g.34860G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:14148812:C:T

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

effect on RNA splicing; Variation Ontology [ VariO:0362]

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.

Links

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.
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.
Xeroderma pigmentosum, group C	Pathogenic (2)	criteria provided, single submitter	Mar 4, 2022	RCV002280586.3

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.
Pathogenic (Mar 04, 2022)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Xeroderma pigmentosum, group C Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004814137.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The XPC c.2250+1G>A variant results in a substitution at the consensus splice donor site, which is predicted to result in splicing defects that may lead … (more) The XPC c.2250+1G>A variant results in a substitution at the consensus splice donor site, which is predicted to result in splicing defects that may lead to a truncated protein. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000033 in the South Asian population (version 3.1.2). This variant was identified in a homozygous state in the proband with a phenotype consistent with xeroderma pigmentosum. Based on the available evidence, the c.2250+1G>A variant is classified as pathogenic for xeroderma pigmentosum. (less)
Pathogenic (Feb 25, 2022)	no assertion criteria provided Method: clinical testing	Xeroderma pigmentosum, group C (Autosomal recessive inheritance) Affected status: yes, no Allele origin: germline	Hacettepe Pediatric Genetics Laboratory, Hacettepe University Accession: SCV002099535.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Publications: pmc: 10766188 pmc: 10766188 Comment: The variant detected in homozygous state in the XPC gene, c.2250+1G>A, is a splice site mutation (splice donor site mutation). It is associated with the … (more) The variant detected in homozygous state in the XPC gene, c.2250+1G>A, is a splice site mutation (splice donor site mutation). It is associated with the phenotype called "Xeroderma pigmentosum, group C". It has not been reported in ClinVar before, and it is suggested to be a pathogenic variant. This variant was neither found in ExAC nor 1000G. This change was classified as “pathogenic” according to the ACMG guidelines and predicted to be disease causing by in silico analysis such as MutationTaster. (less) Observation 1: Number of individuals with the variant: 2 Age: 30-35 years Sex: male Ethnicity/Population group: Turkish Geographic origin: Turkey Observation 2: Age: 10-19 years Sex: male Ethnicity/Population group: Turkish Geographic origin: Turkey

Comment:

The XPC c.2250+1G>A variant results in a substitution at the consensus splice donor site, which is predicted to result in splicing defects that may lead to a truncated protein. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000033 in the South Asian population (version 3.1.2). This variant was identified in a homozygous state in the proband with a phenotype consistent with xeroderma pigmentosum. Based on the available evidence, the c.2250+1G>A variant is classified as pathogenic for xeroderma pigmentosum.

Comment:

The variant detected in homozygous state in the XPC gene, c.2250+1G>A, is a splice site mutation (splice donor site mutation). It is associated with the phenotype called "Xeroderma pigmentosum, group C". It has not been reported in ClinVar before, and it is suggested to be a pathogenic variant. This variant was neither found in ExAC nor 1000G. This change was classified as “pathogenic” according to the ACMG guidelines and predicted to be disease causing by in silico analysis such as MutationTaster.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on RNA splicing (VariO:0362)			Hacettepe Pediatric Genetics Laboratory, Hacettepe University Accession: SCV002099535.1	Publications pmc: 10766188

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Effect of non-invasive neuromodulation techniques on vascular cognitive impairment: A Bayesian network meta-analysis protocol.	Yan L	PloS one	2024	PMC10766188

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_004628.5(XPC):c.2250+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...