NM_000202.8(IDS):c.692C>T (p.Pro231Leu) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 8, 2025
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:: RCV001376687.10

Allele description [Variation Report for NM_000202.8(IDS):c.692C>T (p.Pro231Leu)]

NM_000202.8(IDS):c.692C>T (p.Pro231Leu)

Genes:

LOC106050102:IDS recombination region [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.692C>T (p.Pro231Leu)

HGVS:

NC_000023.11:g.149498123G>A
NG_011900.3:g.12212C>T
NG_042264.1:g.11478G>A
NM_000202.8:c.692C>TMANE SELECT
NM_001166550.4:c.422C>T
NM_006123.5:c.692C>T
NP_000193.1:p.Pro231Leu
NP_001160022.1:p.Pro141Leu
NP_006114.1:p.Pro231Leu
NC_000023.10:g.148579654G>A
NR_104128.2:n.861C>T

Protein change:

P141L

Links:

dbSNP: rs2089450305

NCBI 1000 Genomes Browser:

rs2089450305

Molecular consequence:

NM_000202.8:c.692C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166550.4:c.422C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006123.5:c.692C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104128.2:n.861C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001573772	Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi	no assertion criteria provided	Affects (Apr 3, 2014)	germline	research
SCV003445272	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9762601, 12572848, 27146977, 30639582, 28492532
SCV005089187	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 7, 2024)	germline	literature only	PubMed (7) [See all records that cite these PMIDs] 24125893, 9762601, 33960103, 27146977, 30639582, 36945845, 25741868
SCV007096946	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 8, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27146977, 23232253, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	7	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
INDIAN	germline	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Mucopolysaccharidosis type II--genotype/phenotype aspects.

Froissart R, Moreira da Silva I, Guffon N, Bozon D, Maire I.

Acta Paediatr Suppl. 2002;91(439):82-7.

PubMed [citation]

PMID:: 12572848

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (10)

Details of each submission

From Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, SCV001573772.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	INDIAN	1	not provided	not provided	research	not provided

Description

The change c.692C>T, (p.P231L) was found to be a missense variant, where the cyclic nonpolar neutral amino acid Proline at 231 position was substituted by aliphatic nonpolar neutral amino acid Leucine. It was detected in the hemizygous condition in one case with attenuated phenotype from Delhi, India.

"variation affecting protein" was previously submitted as the functional consequence for NM_000202.8:c.692C>T, but without providing the result of a functional assay.

Description

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003445272.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 231 of the IDS protein (p.Pro231Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 9762601, 12572848, 27146977, 30639582). ClinVar contains an entry for this variant (Variation ID: 1065825). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IDS protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

#	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, SCV005089187.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	literature only	PubMed (7)

Description

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), 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_Moderate)

#	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		7	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV007096946.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has been reported in multiple individuals in the literature with variable severity of mucopolysaccharidosis II ranging from attenuated to severe (PMIDs: 30639582, 27146977, 24125893, 9762601, 36945845, 35144014, 19167723); This variant has moderate functional evidence supporting abnormal protein function. IDS enzyme activity was decreased in an individual who was shown to be hemizygous for this variant (PMID: 27146977); Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change, p.(Pro231Arg), has been classified as likely pathogenic or pathogenic by clinical laboratories in ClinVar; Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from Pro to Leu; This variant is hemizygous; This gene is associated with X-linked disease. Heterozygous females can be asymptomatic or affected similarly to hemizygous males, usually due to skewed X inactivation (PMID: 23232253); Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 1 heterozygote(s), 0 homozygote(s), 0 hemizygote(s)); No published evidence of segregation with disease has been identified for this variant; Variant is located in the annotated sulfatase domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis II (MIM#309900); This variant has been shown to be maternally inherited by trio analysis.

#	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		not provided	not provided	not provided	not provided

Last Updated: Nov 8, 2025

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