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NM_000202.8(IDS):c.1265G>A (p.Cys422Tyr) 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:
RCV000811810.11

Allele description [Variation Report for NM_000202.8(IDS):c.1265G>A (p.Cys422Tyr)]

NM_000202.8(IDS):c.1265G>A (p.Cys422Tyr)

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.1265G>A (p.Cys422Tyr)
HGVS:
  • NC_000023.11:g.149483134C>T
  • NG_011900.3:g.27201G>A
  • NM_000202.8:c.1265G>AMANE SELECT
  • NM_001166550.4:c.995G>A
  • NP_000193.1:p.Cys422Tyr
  • NP_001160022.1:p.Cys332Tyr
  • NC_000023.10:g.148564665C>T
  • NM_000202.6:c.1265G>A
Protein change:
C332Y
Links:
dbSNP: rs886044835
NCBI 1000 Genomes Browser:
rs886044835
Molecular consequence:
  • NM_000202.8:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001166550.4:c.995G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000952097Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Aug 17, 2018)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002014471Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Sep 5, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005089495Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 7, 2024)
germlineliterature only

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes7not providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular basis of mucopolysaccharidosis type II in Portugal: identification of four novel mutations.

Moreira da Silva I, Froissart R, Marques dos Santos H, Caseiro C, Maire I, Bozon D.

Clin Genet. 2001 Oct;60(4):316-8. No abstract available.

PubMed [citation]
PMID:
11683780

Mutation analysis of the iduronate-2-sulfatase gene in patients with mucopolysaccharidosis type II (Hunter syndrome).

Bunge S, Steglich C, Beck M, Rosenkranz W, Schwinger E, Hopwood JJ, Gal A.

Hum Mol Genet. 1992 Aug;1(5):335-9.

PubMed [citation]
PMID:
1303211
See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000952097.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 422 of the IDS protein (p.Cys422Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant has been observed in individuals affected with mucopolysaccharidosis II (PMID: 26762690, 27246110, 24125893). ClinVar contains an entry for this variant (Variation ID: 284860). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the p.Cys422 amino acid residue in IDS have been observed in affected individuals (PMID: 26762690, 27246110, 24125893, 11683780, 1303211, 28077157). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV002014471.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV005089495.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided7not providednot providedliterature only PubMed (7)

Description

In vitro or in vivo functional studies supportive of a damaging effect (PS3_Moderate), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), 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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided7not providednot providednot provided

Last Updated: Sep 29, 2024