VCV000221221.12 - ClinVar

NM_000202.8(IDS):c.708+1G>A

Germline

Classification

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

Pathogenic/Likely pathogenic
Pathogenic (2); Likely pathogenic (1)

3 out of 4 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

Functional data are available for this variant

Variant Details

Identifiers

NM_000202.8(IDS):c.708+1G>A

Variation ID: 221221 Accession: VCV000221221.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 149498106 (GRCh38) [ NCBI UCSC ] X: 148579637 (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	Feb 2, 2016	Feb 15, 2026	Jun 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000202.8:c.708+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001166550.4:c.438+1G>A		splice donor
NM_006123.5:c.708+1G>A		splice donor
NC_000023.11:g.149498106C>T
NC_000023.10:g.148579637C>T
NG_011900.3:g.12229G>A
NG_042264.2:g.11462C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000023.11:149498105:C:T

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

ClinGen: CA348776 dbSNP: rs864622778 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.
IDS		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	743	1764
LOC106050102	-	-	-	GRCh38	-	840

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.
Mucopolysaccharidosis, MPS-II	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 7, 2024	RCV000204551.12

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 (Dec 07, 2011) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2007)	Mucopolysaccharidosis, MPS-II (X-linked inheritance)	IIFP, CONICET-UNLP Accession: SCV000262539.3 First in ClinVar: Feb 02, 2016 Last updated: Aug 03, 2025	Publications: DOI: 10.1016/j.ymgmr.2014.08.006 DOI: 10.1016/j.ymgmr.2014.08.006 Observation: 1 Collection method: research Allele origin: maternal Affected status: yes more Observation 1 Collection method: research Allele origin: maternal Affected status: yes Number of individuals with the variant: 1 Sex: male Geographic origin: Argentina Comment on evidence: "exon loss" was previously submitted as the functional consequence for NM_000202.6:c.708+1G>A, but without providing the result of a functional assay.

Likely pathogenic (Jun 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Mucopolysaccharidosis, MPS-II	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova Accession: SCV005089199.2 First in ClinVar: Aug 04, 2024 Last updated: Apr 13, 2025 Comment: Classification method: ACMG Guidelines [PMID:25741868] with modifications	Publications: PubMed (1) PubMed: 27896113 Comment: show Null variant (PVS1_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) (less) Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes more Observation 1 Collection method: literature only Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Sex: male

Pathogenic (Oct 07, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Mucopolysaccharidosis, MPS-II	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002234986.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 27246110‚ 27896113‚ 31877959‚ 9875019 Comment: show This sequence change affects a donor splice site in intron 5 of the IDS gene. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of mucopolysaccharidosis type II (PMID: 27896113, 27246110, 31877959, 9875019). ClinVar contains an entry for this variant (Variation ID: 221221). Experimental studies have shown that disruption of this splice site affects IDS protein function (PMID: 31877959). Studies have shown that this variant is associated with skipping of exon 5 but is expected to preserve the integrity of the reading frame (PMID: 27896113). 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

Comment:

This sequence change affects a donor splice site in intron 5 of the IDS gene. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of mucopolysaccharidosis type II (PMID: 27896113, 27246110, 31877959, 9875019). ClinVar contains an entry for this variant (Variation ID: 221221). Experimental studies have shown that disruption of this splice site affects IDS protein function (PMID: 31877959). Studies have shown that this variant is associated with skipping of exon 5 but is expected to preserve the integrity of the reading frame (PMID: 27896113). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II).	Lin HY	International journal of molecular sciences	2019	PMID: 31877959
Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase.	Kosuga M	Molecular genetics and metabolism	2016	PMID: 27246110
Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome).	Amartino H	Molecular genetics and metabolism reports	2014	PMID: 27896113
Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease).	Vafiadaki E	Archives of disease in childhood	1998	PMID: 9875019
-	-	-	-	DOI: 10.1016/j.ymgmr.2014.08.006

Submissions - Functional Data

functionally abnormal -- skipped exon

assessed by RNAseq

Result:

junction spanning - exon skipping (p=0.0458)

Modifies a natural donor site at NC_000023.10:g.148579637 from 6.40 to -12.23 bits. Significant p-values: junction spanning - exon skipping (6 reads, p=0.0458). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006994667.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-KN-8421), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Nonpapillary renal cell carcinoma
Transcript: NM_000202.8:c.708+1G>A
Molecular phenotype measured: splicing
Cell line: TCGA-KN-8421
Tissue: Kidney Chromophobe (KICH)
Collection method: in vitro
Species: human
Number of controls: 88

Text-mined citations for rs864622778 ...

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 Apr 13, 2026