VCV001324563.12 - ClinVar

NM_000202.8(IDS):c.104-2A>G

Germline

Classification

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

Pathogenic/Likely pathogenic
Pathogenic (3); Likely pathogenic (1)

4 out of 5 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.104-2A>G

Variation ID: 1324563 Accession: VCV001324563.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 149504295 (GRCh38) [ NCBI UCSC ] X: 148585825 (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	Nov 29, 2021	Feb 23, 2026	Jun 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000202.8:c.104-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001166550.4:c.-123-2A>G		splice acceptor
NM_006123.5:c.104-2A>G		splice acceptor
NC_000023.11:g.149504295T>C
NC_000023.10:g.148585825T>C
NG_011900.3:g.6040A>G
NG_147751.1:g.511T>C
NG_147751.2:g.511T>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000023.11:149504294:T:C

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: CA414527993 dbSNP: rs2089505773 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	744	1765

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 (4)	criteria provided, multiple submitters, no conflicts	Jun 7, 2024	RCV001782283.20

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 (May 20, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Mucopolysaccharidosis, MPS-II	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806923.2 First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023	Comment: show ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Geographic origin: Brazil Method: Paired-end whole-genome sequencing

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: SCV005089101.2 First in ClinVar: Aug 04, 2024 Last updated: Apr 13, 2025 Comment: Classification method: ACMG Guidelines [PMID:25741868] with modifications	Publications: PubMed (6) PubMed: 11683780‚ 17063374‚ 33676511‚ 35144014‚ 9875019‚ 9921913 Comment: show Null variant (PVS1_VeryStrong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), 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: 6 Sex: male

Likely pathogenic (Jan 11, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Mucopolysaccharidosis, MPS-II	Revvity Omics, Revvity Accession: SCV002016663.4 First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 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 (Jan 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Mucopolysaccharidosis, MPS-II	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004298744.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (4) PubMed: 16199547‚ 33676511‚ 8940265‚ 9875019 Comment: show This sequence change affects an acceptor splice site in intron 1 of the IDS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDS are known to be pathogenic (PMID: 8940265, 9875019). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis II (PMID: 33676511). This variant is also known as 228–2A>G. ClinVar contains an entry for this variant (Variation ID: 1324563). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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:

Null variant (PVS1_VeryStrong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), 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)

Comment:

This sequence change affects an acceptor splice site in intron 1 of the IDS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDS are known to be pathogenic (PMID: 8940265, 9875019). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis II (PMID: 33676511). This variant is also known as 228–2A>G. ClinVar contains an entry for this variant (Variation ID: 1324563). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-phenotype spectrum of 130 unrelated Indian families with Mucopolysaccharidosis type II.	Agrawal N	European journal of medical genetics	2022	PMID: 35144014
Analysis of long-term observations of the large group of Russian patients with Hunter syndrome (mucopolysaccharidosis type II).	Semyachkina AN	BMC medical genomics	2021	PMID: 33676511
Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations.	Alves S	Journal of inherited metabolic disease	2006	PMID: 17063374
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Molecular basis of mucopolysaccharidosis type II in Portugal: identification of four novel mutations.	Moreira da Silva I	Clinical genetics	2001	PMID: 11683780
Mutational spectrum of the iduronate-2-sulfatase (IDS) gene in 36 unrelated Russian MPS II patients.	Karsten S	Human genetics	1998	PMID: 9921913
Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease).	Vafiadaki E	Archives of disease in childhood	1998	PMID: 9875019
Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene.	Rathmann M	American journal of human genetics	1996	PMID: 8940265

Submissions - Functional Data

functionally abnormal -- retained intron

assessed by RNAseq

Result:

read abundance - intron inclusion (p=0.0428)

Modifies a natural acceptor site at NC_000023.10:g.148585824 from 4.11 to -10.60 bits. Significant p-values: read abundance - intron inclusion (27 reads, p=0.0428). 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: SCV006994702.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-KN-8437), 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.104-2A>G
Molecular phenotype measured: splicing
Cell line: TCGA-KN-8437
Tissue: Kidney Chromophobe (KICH)
Collection method: in vitro
Species: human
Number of controls: 87

Text-mined citations for rs2089505773 ...

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