NM_000202.8(IDS):c.998C>T (p.Ser333Leu) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Pathogenic (10 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:: RCV000011233.32

Allele description [Variation Report for NM_000202.8(IDS):c.998C>T (p.Ser333Leu)]

NM_000202.8(IDS):c.998C>T (p.Ser333Leu)

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.998C>T (p.Ser333Leu)

HGVS:

NC_000023.11:g.149490322G>A
NG_011900.3:g.20013C>T
NG_042264.1:g.3677G>A
NM_000202.8:c.998C>TMANE SELECT
NM_001166550.4:c.728C>T
NM_006123.5:c.998C>T
NP_000193.1:p.Ser333Leu
NP_000193.1:p.Ser333Leu
NP_001160022.1:p.Ser243Leu
NP_006114.1:p.Ser333Leu
NC_000023.10:g.148571853G>A
NM_000202.4:c.998C>T
NM_000202.5:c.998C>T
NM_000202.6:c.998C>T
NR_104128.2:n.1297C>T
P22304:p.Ser333Leu

Protein change:

S243L; SER333LEU

Links:

UniProtKB: P22304#VAR_007360; OMIM: 300823.0002; dbSNP: rs104894853

NCBI 1000 Genomes Browser:

rs104894853

Molecular consequence:

NM_000202.8:c.998C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166550.4:c.728C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006123.5:c.998C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104128.2:n.1297C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

variation affecting protein [Variation Ontology: 0002]

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
SCV000031460	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1992)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000262529	IIFP, CONICET-UNLP	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Apr 16, 2010)	maternal	research	PubMed (1) [See all records that cite this PMID]
SCV000999926	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001207067	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 29, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1639384, 30639582, 17091340, 28543354, 28492532
SCV001480194	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001573787	Pediatrics, All India Institute of Medical Sciences, New Delhi	no assertion criteria provided	Affects (Apr 7, 2014)	germline	research
SCV002014474	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002575080	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	no assertion criteria provided	Pathogenic	maternal	provider interpretation
SCV005042552	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005089333	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 (33) [See all records that cite these PMIDs] 35144014, 27351199, 27896113, 24125893, 27883178, 1639384, 9660053, 35005816, 8111411, 9501270, 7887413, 33960103, 9921913, 27246110, 8830188, 9950361, 31877959, 16495038, 8566953, 14728992, 15500445, 8940265, 33676511, 21291454, 7581397, 9875019, 28543354, 34258227, 21829674, 30639582, 36713083, 36945845, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	64	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	2	2	not provided	not provided	not provided	research, provider interpretation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
INDIAN	germline	yes	1	not provided	not provided	not provided	not provided	research
Indian	germline	yes	4	4	not provided	not provided	not provided	clinical testing

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

Mucopolysaccharidosis Type II.

Scarpa M.

2007 Nov 6 [updated 2024 Apr 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301451

See all PubMed Citations (37)

Details of each submission

From OMIM, SCV000031460.2

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

Description

In their patient 4 with Hunter syndrome (309900), Flomen et al. (1992) identified a C-to-T transition at nucleotide 1122 in the IDS gene, resulting in substitution of leucine for serine-333, which is a conserved residue within a region of homology among sulfatases. This mutation creates a novel splice site that is preferentially used and results in partial loss of 1 exon in the RNA.

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

From IIFP, CONICET-UNLP, SCV000262529.1

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

#	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		2	not provided	2	not provided

From GeneReviews, SCV000999926.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001207067.5

#	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 serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 333 of the IDS protein (p.Ser333Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type II (MPS II) (PMID: 1639384, 28543354, 30639582; Invitae). ClinVar contains an entry for this variant (Variation ID: 10487). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects IDS function (PMID: 17091340, 28543354). 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 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, SCV001480194.1

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

#	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		4	not provided	4	not provided

From Pediatrics, All India Institute of Medical Sciences, New Delhi, SCV001573787.1

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

Description

The change c.998C>T (p.S333L) was found to be a missense variant, where the hydroxyl-containing polar neutral amino acid Serine at 333 position was substituted by aliphatic nonpolar neutral amino acid Leucine. It was detected in a hemizygous state in one case with severe phenotype from Haryana, India.

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 Genome-Nilou Lab, SCV002014474.1

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

#	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 Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University, SCV002575080.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	provider interpretation	not provided

#	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		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042552.1

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

Description

The missense variant c.998C>Tp.Ser333Leu in IDS gene has been reported previously in hemizygous state in most of the individuals with mucopolysaccharidosis type II. Experimental studies have shown that this missense change affects IDS function Sukegawa-Hayasaka K, et al., 2006, Vollebregt AAM, et al., 2017. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions.The amino acid Serine at position 333 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Ser333Leu in IDS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	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, SCV005089333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	64	not provided	not provided	literature only	PubMed (33)

Description

In vitro or in vivo functional studies supportive of a damaging effect (PS3_Strong), 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_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		64	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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