NM_000202.8(IDS):c.1589dup (p.Leu530fs) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Pathogenic (2 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:: RCV001946683.5

Allele description [Variation Report for NM_000202.8(IDS):c.1589dup (p.Leu530fs)]

NM_000202.8(IDS):c.1589dup (p.Leu530fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000202.8(IDS):c.1589dup (p.Leu530fs)

HGVS:

NC_000023.11:g.149482811dup
NG_011900.3:g.27525dup
NM_000202.8:c.1589dupMANE SELECT
NM_001166550.4:c.1319dup
NP_000193.1:p.Leu530fs
NP_001160022.1:p.Leu440fs
NC_000023.10:g.148564340_148564341insA
NC_000023.10:g.148564342dup

Protein change:

L440fs

Links:

dbSNP: rs2124648266

NCBI 1000 Genomes Browser:

rs2124648266

Molecular consequence:

NM_000202.8:c.1589dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001166550.4:c.1319dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002232154	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 24, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17284421, 7581397, 28492532
SCV005089639	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] 17284421, 36945845, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002232154

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 24, 2021)

germline

clinical testing

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

SCV005089639

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	yes	2	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

Citations

PubMed

Mucopolysaccharidosis type II (Hunter disease): identification and characterization of eight point mutations in the iduronate-2-sulfatase gene in Japanese patients.

Sukegawa K, Tomatsu S, Fukao T, Iwata H, Song XQ, Yamada Y, Fukuda S, Isogai K, Orii T.

Hum Mutat. 1995;6(2):136-43.

PubMed [citation]

PMID:: 7581397

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 (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002232154.3

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

Description

This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type II (PMID: 17284421; external communication). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu530Phefs*8) in the IDS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the IDS protein. This variant is also known as c.1587~1588insT . For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IDS protein in which other variant(s) (p.Gln531*) have been determined to be pathogenic (PMID: 7581397). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

#	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, SCV005089639.1

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

Description

Null variant (PVS1_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		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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