NM_000202.8(IDS):c.1403G>A (p.Arg468Gln) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Pathogenic (8 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:: RCV000180473.24

Allele description [Variation Report for NM_000202.8(IDS):c.1403G>A (p.Arg468Gln)]

NM_000202.8(IDS):c.1403G>A (p.Arg468Gln)

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.1403G>A (p.Arg468Gln)

HGVS:

NC_000023.11:g.149482996C>T
NG_011900.3:g.27339G>A
NM_000202.8:c.1403G>AMANE SELECT
NM_001166550.4:c.1133G>A
NP_000193.1:p.Arg468Gln
NP_000193.1:p.Arg468Gln
NP_001160022.1:p.Arg378Gln
NC_000023.10:g.148564527C>T
NM_000202.5:c.1403G>A
NM_000202.6:c.1403G>A
NM_000202.7:c.1403G>A
P22304:p.Arg468Gln

Protein change:

R378Q; ARG468GLN

Links:

UniProtKB: P22304#VAR_007377; OMIM: 300823.0013; dbSNP: rs113993946

NCBI 1000 Genomes Browser:

rs113993946

Molecular consequence:

NM_000202.8:c.1403G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001166550.4:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Selenohomolysine (0)
ClinVar
R.norvegicus mRNA for heat shock related protein
R.norvegicus mRNA for heat shock related protein
gi|1155015|emb|X82021.1|

Nucleotide
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Agononida procera voucher Fo119 cytochrome oxidase subunit I (COI) gene, partial cds; mitochondrial
gi|38044365|gb|AY350917.1|

Nucleotide
zw03g04.r1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE:768246 5', mRNA sequen...
zw03g04.r1 Soares_NhHMPu_S1 Homo sapiens cDNA clone IMAGE:768246 5', mRNA sequence
gi|2107025|gnl|dbEST|1070039|gb|AA4 .1|

Nucleotide
Scleroderma, Limited
Scleroderma, Limited
The least progressive form of SYSTEMIC SCLERODERMA with skin thickening restricted to the face, neck and areas distal to the elbows and/or knees, sparing the trunk. The CREST ...<br/>Year introduced: 2004

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000262515	IIFP, CONICET-UNLP	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Aug 2, 2007)	maternal, de novo, unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000929887	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 (39) [See all records that cite these PMIDs] 35144014, 26762690, 27896113, 24125893, 28077157, 24798265, 27883178, 34813777, 11462244, 9660053, 25681085, 8664909, 35225932, 8111411, 9501270, 33960103, 9921913, 18500569, 27246110, 9950361, 9266380, 11683780, 14728992, 8940265, 27187040, 33676511, 32775211, 21291454, 7581397, 9375851, 27146977, 9875019, 9222763, 8364592, 30639582, 34670126, 36945845, 25741868, 30809705 Citation Link,
SCV000999927	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001480198	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]
SCV002014467	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]
SCV003825334	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003915848	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004299009	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 25, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1284597, 15614569, 28077157, 30639582, 18500569, 7581397, 9266380, 9875019, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	1	not provided	not provided	not provided	research
not provided	germline	yes	91	not provided	not provided	not provided	not provided	literature only, clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	de novo	yes	1	1	not provided	not provided	not provided	research
not provided	maternal	yes	4	1	not provided	not provided	not provided	research
Indian	germline	yes	1	not provided	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

Genotype-phenotype spectrum of 130 unrelated Indian families with Mucopolysaccharidosis type II.

Agrawal N, Verma G, Saxena D, Kabra M, Gupta N, Mandal K, Moirangthem A, Sheth J, Puri RD, Bijarnia-Mahay S, Kapoor S, Danda S, H SV, Datar CA, Ranganath P, Shukla A, Dalal A, Srivastava P, Devi RR, Phadke SR.

Eur J Med Genet. 2022 Mar;65(3):104447. doi: 10.1016/j.ejmg.2022.104447. Epub 2022 Feb 8.

PubMed [citation]

PMID:: 35144014

See all PubMed Citations (44)

Details of each submission

From IIFP, CONICET-UNLP, SCV000262515.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	research	PubMed (1)
2	not provided	1	not provided	not provided	research	PubMed (1)
3	not provided	1	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		4	not provided	1	not provided
2	de novo	yes	not provided	not provided	not provided		1	not provided	1	not provided
3	unknown	yes	not provided	not provided	not provided		1	not provided	1	not provided

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV000929887.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	90	not provided	not provided	literature only	PubMed (39)

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_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Cosegregation with disease in multiple affected family members (PP1_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		90	not provided	not provided	not provided

From GeneReviews, SCV000999927.2

#	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 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, SCV001480198.1

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

From Genome-Nilou Lab, SCV002014467.1

#	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 Revvity Omics, Revvity, SCV003825334.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV003915848.1

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

Description

A hemizygous variation in exon 9 of the IDS gene detected. The observed variant c.1403G>A has not been reported in the 1000 genomes databases. The in silico prediction is damaging by SIFT, PROVEAN, Polyphen2 and MutationTaster. In summary, the variant meets our criteria to be 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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004299009.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg468 amino acid residue in IDS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1284597, 15614569, 28077157, 30639582). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects IDS function (PMID: 18500569). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDS protein function. ClinVar contains an entry for this variant (Variation ID: 10498). This missense change has been observed in individuals with mucopolysaccharidosis II (PMID: 7581397, 9266380, 9875019). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 468 of the IDS protein (p.Arg468Gln).

#	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

Last Updated: Oct 26, 2024

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