NM_000202.8(IDS):c.133G>C (p.Asp45His) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 7, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000207419.10

Allele description [Variation Report for NM_000202.8(IDS):c.133G>C (p.Asp45His)]

NM_000202.8(IDS):c.133G>C (p.Asp45His)

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.133G>C (p.Asp45His)

HGVS:

NC_000023.11:g.149504264C>G
NG_011900.3:g.6071G>C
NM_000202.8:c.133G>CMANE SELECT
NM_001166550.4:c.-94G>C
NM_006123.5:c.133G>C
NP_000193.1:p.Asp45His
NP_006114.1:p.Asp45His
NC_000023.10:g.148585794C>G
NM_000202.6:c.133G>C
NR_104128.2:n.302G>C

Protein change:

D45H

Links:

dbSNP: rs869025301

Molecular consequence:

NM_001166550.4:c.-94G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000202.8:c.133G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006123.5:c.133G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_104128.2:n.302G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-II (MPS2)
Synonyms:: Attenuated MPS (subtype; formerly known as mild MPS II); Severe MPS II; I2S deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010674; MedGen: C0026705; Orphanet: 580; OMIM: 309900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000262703	MOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIA	criteria provided, single submitter (ACMG Guidelines, 2007)	Likely pathogenic (Oct 18, 2015)	maternal	research	PubMed (2) [See all records that cite these PMIDs] 18414213, 26762690
SCV001576860	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9875019, 24125893, 26762690, 28492532
SCV005089243	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 (2) [See all records that cite these PMIDs] 26762690, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000262703

MOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIA

criteria provided, single submitter

(ACMG Guidelines, 2007)

Likely pathogenic
(Oct 18, 2015)

maternal

research

PubMed (2)
[See all records that cite these PMIDs]

SCV001576860

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 14, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005089243

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 (2)
[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	yes	1	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Mexican	maternal	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee.

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease).

Vafiadaki E, Cooper A, Heptinstall LE, Hatton CE, Thornley M, Wraith JE.

Arch Dis Child. 1998 Sep;79(3):237-41.

PubMed [citation]

PMID:: 9875019
PMCID:: PMC1717680

See all PubMed Citations (6)

Details of each submission

From MOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIA, SCV000262703.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Mexican	1	not provided	not provided	research	PubMed (2)

Description

Likely pathogenic variation identified in a Hunter syndrome male patient without I2S evaluation. He presents mental retardation and seizures. No hydrocephaly. Pathogenicity clues: Highly conserved nucleotide (phyloP: 0.86 [-5.2;1.1]); Highly conserved amino acid, up to Fruitfly (considering 12 species); Moderate physicochemical difference between Asp and His (Grantham dist.: 81 [0-215]); This variant is in protein domains: Sulfatase, Alkaline-phosphatase-like, core domain, Align GVGD: C0 (GV: 213.16 - GD: 59.84); SIFT: Deleterious (score: 0, median: 3.50); MutationTaster: disease causing (p-value: 1); Polyphen prediction: Probably Damaging (HumDiv score 1.0)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001576860.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp45 amino acid residue in IDS. Other variant(s) that disrupt this residue have been observed in individuals with IDS-related conditions (PMID: 9875019, 24125893), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDS protein function. ClinVar contains an entry for this variant (Variation ID: 221970). This missense change has been observed in individual(s) with mucopolysaccharidosis type II (PMID: 26762690; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 45 of the IDS protein (p.Asp45His).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	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, SCV005089243.2

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

Description

Located in a mutational hot spot and/or critical functional domain (PM1_Moderate), 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		1	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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