NM_000202.8(IDS):c.1454T>C (p.Ile485Thr) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 7, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003985699.3

Allele description [Variation Report for NM_000202.8(IDS):c.1454T>C (p.Ile485Thr)]

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

Gene:

IDS:iduronate 2-sulfatase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

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

HGVS:

NC_000023.11:g.149482945A>G
NG_011900.3:g.27390T>C
NM_000202.8:c.1454T>CMANE SELECT
NM_001166550.4:c.1184T>C
NP_000193.1:p.Ile485Thr
NP_001160022.1:p.Ile395Thr
NC_000023.10:g.148564476A>G

Protein change:

I395T

Molecular consequence:

NM_000202.8:c.1454T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001166550.4:c.1184T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-II (MPS2)
Synonyms:: Mucopolysaccharidosis type II; Attenuated MPS (subtype; formerly known as mild MPS II); Severe MPS II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010674; MedGen: C0026705; Orphanet: 580; OMIM: 309900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004801331	Serv. Biochemistry and Molecular genetics, Hospital Clinic de Barcelona, Hospital Clínic de Barcelona	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Mar 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005089592	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 7, 2024)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 33960103, 16770800, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004801331

Serv. Biochemistry and Molecular genetics, Hospital Clinic de Barcelona, Hospital Clínic de Barcelona

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Mar 18, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005089592

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 7, 2024)

germline

literature only

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Genotype-phenotype studies in a large cohort of Brazilian patients with Hunter syndrome.

Josahkian JA, Brusius-Facchin AC, Netto ABO, Leistner-Segal S, Málaga DR, Burin MG, Michelin-Tirelli K, Trapp FB, Cardoso-Dos-Santos AC, Ribeiro EM, Kim CA, de Siqueira ACM, Santos ML, do Valle DA, da Silva RTB, Horovitz DDG, de Medeiros PFV, de Souza CFM, Giuliani LR, Miguel DSCG, Santana-da-Silva LC, Galera MF, et al.

Am J Med Genet C Semin Med Genet. 2021 Sep;187(3):349-356. doi: 10.1002/ajmg.c.31915. Epub 2021 May 7. Erratum in: Am J Med Genet C Semin Med Genet. 2022 Sep;190(3):405-406. doi: 10.1002/ajmg.c.31971.

PubMed [citation]

PMID:: 33960103

Further cases of "neighbor" mutations in mucopolysaccharidosis type II.

Schwartz IV, Lima LC, Tylee K, Sobrinho RP, Norato DY, Duarte AR, Besley G, Burin MG, Matte U, Giugliani R, Leistner-Segal S.

Am J Med Genet A. 2006 Aug 1;140(15):1684-6. No abstract available.

PubMed [citation]

PMID:: 16770800

See all PubMed Citations (3)

Details of each submission

From Serv. Biochemistry and Molecular genetics, Hospital Clinic de Barcelona, Hospital Clínic de Barcelona, SCV004801331.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV005089592.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	literature only	PubMed (3)

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Aug 4, 2024

ClinVar

Relating variation to medicine