VCV003062164.4 - ClinVar

NM_000202.8(IDS):c.1454T>C (p.Ile485Thr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic (1); Benign (1); Likely benign (1)

3 out of 3 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_000202.8(IDS):c.1454T>C (p.Ile485Thr)

Variation ID: 3062164 Accession: VCV003062164.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 149482945 (GRCh38) [ NCBI UCSC ] X: 148564476 (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	Mar 23, 2024	Oct 12, 2025	Sep 10, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000202.8:c.1454T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000193.1:p.Ile485Thr	missense
NM_001166550.4:c.1184T>C	NP_001160022.1:p.Ile395Thr	missense
NC_000023.11:g.149482945A>G
NC_000023.10:g.148564476A>G
NG_011900.3:g.27390T>C

... more HGVS ... less HGVS

Protein change

I395T, I485T

Other names

Canonical SPDI

NC_000023.11:149482944:A:G

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA10537443 dbSNP: rs782430567 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	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Sep 10, 2025	RCV003985699.6

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.
Benign (Mar 18, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Mucopolysaccharidosis, MPS-II (X-linked recessive inheritance)	Serv. Biochemistry and Molecular genetics, Hospital Clinic de Barcelona, Hospital Clínic de Barcelona Accession: SCV004801331.2 First in ClinVar: Mar 23, 2024 Last updated: Apr 13, 2025	Comment: show Mucopolysaccharidosis type 2 or Hunter disease is a recessive X-linked disorder due to mutations in IDS gene. This gene codifies for iduronate-2-sulfatase, and enzyme crucial in the degradation of heparan and dermatan sulfate. We found the c.1454T>C (p.Ile485Thr) in the IDS gene in hemizygosity in a 2-year-old healthy boy. This variant could be classified as likely pathogenic if we apply the following criteria based on the ACMG guidelines: PP2, PP3, PM1, PM2, PM5. It is the rs782430567 in dbSNP. In ClinVar it is reported with the accession RCV001568383.1. It is not reported in HGMD although there is a variant reported as pathogenic in the same base: c.1454T>A (p.Ile485Lys). We then performed the iduronate-2-sulfatase enzymatic activity in leukocytes of the patient, and it was of 27 nmol/4h/mg prot (control range 18-69 nmol/4h/mg prot), so it was completely normal. His mother and his maternal grandmother were also carriers of the variant. We then analysed the patient's maternal uncle. He was a 37 years-old healthy man, and he was also found to be a carrier of the mutation in hemizygosity. We tested the iduronate-2-sulfatase enzymatic activity in leukocytes of this uncle and it was of 26.3 nmol/4h/mg prot (control range 18-69 nmol/4h/mg prot). The activity was also tested in Dried Blood Spots (DBS) and it was of 5.4 micromol/L.h (control range 3.2-8.5 micromol/L.h). Taking into account that the uncle was a carrier, that at 37 years old he was healthy and that the iduronate-2-sulfatase enzymatic activity tested in leukocytes and in DBS was absolutely normal in both males, we consider this variant as BENIGN (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Sex: male Comment on evidence: We performed iduronate-2-sulfatase activity in males of the family that were hemizygous for the variant and it was completely normal. Furthermore, they were asymptomatic, not … (more) We performed iduronate-2-sulfatase activity in males of the family that were hemizygous for the variant and it was completely normal. Furthermore, they were asymptomatic, not affected. Glucosaminoglican excretion was also normal. (less)

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: SCV005089592.2 First in ClinVar: Aug 04, 2024 Last updated: Apr 13, 2025 Comment: Classification method: ACMG Guidelines [PMID:25741868] with modifications	Publications: PubMed (2) PubMed: 16770800‚ 33960103 Comment: show Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Strong) (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: 2 Sex: male

Likely benign (Sep 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Mucopolysaccharidosis, MPS-II	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV006551701.1 First in ClinVar: Oct 12, 2025 Last updated: Oct 12, 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

Comment:

Mucopolysaccharidosis type 2 or Hunter disease is a recessive X-linked disorder due to mutations in IDS gene. This gene codifies for iduronate-2-sulfatase, and enzyme crucial in the degradation of heparan and dermatan sulfate. We found the c.1454T>C (p.Ile485Thr) in the IDS gene in hemizygosity in a 2-year-old healthy boy. This variant could be classified as likely pathogenic if we apply the following criteria based on the ACMG guidelines: PP2, PP3, PM1, PM2, PM5. It is the rs782430567 in dbSNP. In ClinVar it is reported with the accession RCV001568383.1. It is not reported in HGMD although there is a variant reported as pathogenic in the same base: c.1454T>A (p.Ile485Lys). We then performed the iduronate-2-sulfatase enzymatic activity in leukocytes of the patient, and it was of 27 nmol/4h/mg prot (control range 18-69 nmol/4h/mg prot), so it was completely normal. His mother and his maternal grandmother were also carriers of the variant. We then analysed the patient's maternal uncle. He was a 37 years-old healthy man, and he was also found to be a carrier of the mutation in hemizygosity. We tested the iduronate-2-sulfatase enzymatic activity in leukocytes of this uncle and it was of 26.3 nmol/4h/mg prot (control range 18-69 nmol/4h/mg prot). The activity was also tested in Dried Blood Spots (DBS) and it was of 5.4 micromol/L.h (control range 3.2-8.5 micromol/L.h). Taking into account that the uncle was a carrier, that at 37 years old he was healthy and that the iduronate-2-sulfatase enzymatic activity tested in leukocytes and in DBS was absolutely normal in both males, we consider this variant as BENIGN

Comment:

Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Strong)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-phenotype studies in a large cohort of Brazilian patients with Hunter syndrome.	Josahkian JA	American journal of medical genetics. Part C, Seminars in medical genetics	2021	PMID: 33960103
Further cases of "neighbor" mutations in mucopolysaccharidosis type II.	Schwartz IV	American journal of medical genetics. Part A	2006	PMID: 16770800

Text-mined citations for rs782430567 ...

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