NM_000202.8(IDS):c.389C>T (p.Thr130Ile) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 7, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000632181.9

Allele description [Variation Report for NM_000202.8(IDS):c.389C>T (p.Thr130Ile)]

NM_000202.8(IDS):c.389C>T (p.Thr130Ile)

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.389C>T (p.Thr130Ile)

HGVS:

NC_000023.11:g.149503341G>A
NG_011900.3:g.6994C>T
NM_000202.8:c.389C>TMANE SELECT
NM_001166550.4:c.119C>T
NM_006123.5:c.389C>T
NP_000193.1:p.Thr130Ile
NP_001160022.1:p.Thr40Ile
NP_006114.1:p.Thr130Ile
NC_000023.10:g.148584871G>A
NM_000202.6:c.389C>T
NR_104128.2:n.558C>T

Protein change:

T130I

Links:

dbSNP: rs1557340233

NCBI 1000 Genomes Browser:

rs1557340233

Molecular consequence:

NM_000202.8:c.389C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166550.4:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006123.5:c.389C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104128.2:n.558C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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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Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000753286	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 13, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21829674, 28492532
SCV005089016	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 (3) [See all records that cite these PMIDs] 24125893, 21829674, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000753286

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005089016

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 (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

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

Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.

Brusius-Facchin AC, Schwartz IV, Zimmer C, Ribeiro MG, Acosta AX, Horovitz D, Monlleó IL, Fontes MI, Fett-Conte A, Sobrinho RP, Duarte AR, Boy R, Mabe P, Ascurra M, de Michelena M, Tylee KL, Besley GT, Garreton MC, Giugliani R, Leistner-Segal S.

Mol Genet Metab. 2014 Feb;111(2):133-8. doi: 10.1016/j.ymgme.2013.08.011. Epub 2013 Sep 1.

PubMed [citation]

PMID:: 24125893

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000753286.5

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual affected with mucopolysaccharidosis type II (PMID: 21829674). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 130 of the IDS protein (p.Thr130Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine.

#	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, SCV005089016.1

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

Description

Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense change at the same amino acid residue as a pathogenic variant (PM5_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		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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