NM_000202.8(IDS):c.596_599del (p.Lys199fs) AND Mucopolysaccharidosis, MPS-II

Germline classification:: 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:: RCV001243493.15

Allele description [Variation Report for NM_000202.8(IDS):c.596_599del (p.Lys199fs)]

NM_000202.8(IDS):c.596_599del (p.Lys199fs)

Genes:

LOC106050102:IDS recombination region [Gene]
IDS:iduronate 2-sulfatase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000202.8(IDS):c.596_599del (p.Lys199fs)

HGVS:

NC_000023.11:g.149498219_149498222del
NG_011900.3:g.12116_12119del
NG_042264.1:g.11574_11577del
NM_000202.8:c.596_599delMANE SELECT
NM_001166550.4:c.326_329del
NM_006123.5:c.596_599del
NP_000193.1:p.Lys199fs
NP_001160022.1:p.Lys109fs
NP_006114.1:p.Lys199fs
NC_000023.10:g.148579747_148579750del
NC_000023.10:g.148579750_148579753del
NM_000202.6:c.596_599del
NM_000202.8:c.596_599delAACAMANE SELECT
NR_104128.2:n.765_768del

Protein change:

K109fs

Links:

dbSNP: rs2089451657

Molecular consequence:

NM_000202.8:c.596_599del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001166550.4:c.326_329del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_006123.5:c.596_599del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_104128.2:n.765_768del - 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
SCV001416657	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8940265, 9875019, 7866405, 26762690, 28492532
SCV001572769	Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi	no assertion criteria provided	Likely pathogenic (Jul 1, 2014)	germline	research
SCV005089137	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 (13) [See all records that cite these PMIDs] 35144014, 26762690, 24780617, 34813777, 9501270, 9950361, 33676511, 21291454, 10220152, 21829674, 36713083, 36945845, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001416657

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 15, 2019)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001572769

Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi

no assertion criteria provided

Likely pathogenic
(Jul 1, 2014)

germline

research

SCV005089137

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 (13)
[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	21	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
INDIAN	germline	yes	3	2	not provided	not provided	not provided	research

Citations

PubMed

Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene.

Rathmann M, Bunge S, Beck M, Kresse H, Tylki-Szymanska A, Gal A.

Am J Hum Genet. 1996 Dec;59(6):1202-9.

PubMed [citation]

PMID:: 8940265
PMCID:: PMC1914889

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 (17)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001416657.7

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

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in IDS are known to be pathogenic (PMID: 8940265, 9875019). This variant has been observed in individual(s) with Hunter syndrome (PMID: 7866405, 26762690). This variant is also known as 717del4 in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys199Argfs*13) in the IDS gene. It is expected to result in an absent or disrupted protein product.

#	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 Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, SCV001572769.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	INDIAN	3	not provided	not provided	research	not provided

Description

The change c.596_599delAACA, (p.K199Rfs*13) was found to be a novel small frame-shift deletion variant in which four base deletion leads to frameshift change in the ORF of the translated peptide leading to the substitution of basic polar amino acid Lysine at 199 position by another basic polar amino acid Arginine. This leads to change in peptide sequence and formation of a stop codon 13 amino acid downstream the mutation. In silico analysis by the web tool Mutation Taster characterise it as a ""Disease causing"" pathogenic variant. It was detected in two families, one with two affected male sibs and other with the single affected male patient all were presented with attenuated phenotypes and hailed from Delhi.

"mutation affecting reading frame" was previously submitted as the functional consequence for NM_000202.8:c.596_599delAACA, but without providing the result of a functional assay.

Description

The change c.596_599delAACA, (p.K199Rfs*13) was found to be a novel small frame-shift deletion variant in which four base deletion leads to frameshift change in the ORF of the translated peptide leading to the substitution of basic polar amino acid Lysine at 199 position by another basic polar amino acid Arginine. This leads to change in peptide sequence and formation of a stop codon 13 amino acid downstream the mutation. In silico analysis by the web tool Mutation Taster characterise it as a "Disease causing" pathogenic variant. It was detected in two families, one with two affected male sibs and other with the single affected male patient all were presented with attenuated phenotypes and hailed from Delhi.

#	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		3	not provided	2	not provided

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV005089137.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	21	not provided	not provided	literature only	PubMed (13)

Description

Null variant (PVS1_VeryStrong), 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), 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		21	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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