VCV000092617.20 - ClinVar

NM_000202.8(IDS):c.253G>A (p.Ala85Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000202.8(IDS):c.253G>A (p.Ala85Thr)

Variation ID: 92617 Accession: VCV000092617.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 149503477 (GRCh38) [ NCBI UCSC ] X: 148585007 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 28, 2015	Aug 4, 2024	Jun 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000202.8:c.253G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000193.1:p.Ala85Thr	missense
NM_000202.7:c.253G>A
NM_001166550.4:c.15-32G>A		intron variant
NM_006123.5:c.253G>A	NP_006114.1:p.Ala85Thr	missense
NR_104128.2:n.422G>A		non-coding transcript variant
NC_000023.11:g.149503477C>T
NC_000023.10:g.148585007C>T
NG_011900.3:g.6858G>A
	P22304:p.Ala85Thr

... more HGVS ... less HGVS

Protein change

A85T

Other names

Canonical SPDI

NC_000023.11:149503476:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

variation affecting protein; Variation Ontology [ VariO:0002]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA331781 UniProtKB: P22304#VAR_007319 dbSNP: rs113993949 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
IDS		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	663	1580

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mucopolysaccharidosis, MPS-II	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jun 7, 2024	RCV000177016.26
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 5, 2012	RCV000790731.12

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 16, 2007)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: research	Mucopolysaccharidosis, MPS-II (X-linked inheritance) Affected status: yes Allele origin: unknown	IIFP, CONICET-UNLP Accession: SCV000262519.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Publications: DOI: 10.1016/j.ymgmr.2014.08.006 DOI: 10.1016/j.ymgmr.2014.08.006 Number of individuals with the variant: 2 Sex: male Geographic origin: Argentina
Pathogenic (Sep 05, 2012)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000228820.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDS Number of individuals with the variant: 1 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences Accession: SCV001479333.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Hearing impairment (present) , Motor delay (present) , Coarse facial features (present) , Depressed nasal bridge (present) , Short stature (present) , Macrocephaly (present) , … (more) Hearing impairment (present) , Motor delay (present) , Coarse facial features (present) , Depressed nasal bridge (present) , Short stature (present) , Macrocephaly (present) , Umbilical hernia (present) , Hepatosplenomegaly (present) , Dysostosis multiplex (present) , Flexion contracture (present) (less) Age: 0-9 years Sex: male Ethnicity/Population group: Indian Geographic origin: North India
Pathogenic (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002014484.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002053783.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Jan 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807057.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PP1 supporting, PP3 supporting, PP4 Number of individuals with the variant: 1 Clinical Features: Decreased body weight (present) , Joint stiffness (present) , Skeletal dysplasia (present) , Hepatomegaly (present) , Umbilical hernia (present) , Short stature (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Likely pathogenic (Nov 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003829533.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jun 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003445854.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 17091340‚ 8940265‚ 25976201‚ 26762690‚ 31877959 Comment: ClinVar contains an entry for this variant (Variation ID: 92617). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that … (more) ClinVar contains an entry for this variant (Variation ID: 92617). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IDS function (PMID: 17091340). 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) performed at Invitae indicates that this missense variant is expected to disrupt IDS protein function. This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 8940265, 25976201, 26762690, 31877959). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 85 of the IDS protein (p.Ala85Thr). (less)
Pathogenic (Jun 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: literature only	Mucopolysaccharidosis, MPS-II Affected status: yes Allele origin: germline	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova Accession: SCV005088932.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 Comment: Classification method: ACMG Guidelines [PMID:25741868] with modifications	Publications: PubMed (19) PubMed: 35144014‚ 26762690‚ 27351199‚ 27896113‚ 24125893‚ 15614569‚ 27883178‚ 9660053‚ 9452044‚ 9501270‚ 33960103‚ 27246110‚ 9950361‚ 31877959‚ 8940265‚ 33676511‚ 21291454‚ 27146977‚ 36945845 Comment: 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 … (more) 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), 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) (less) Number of individuals with the variant: 38 Sex: male
Pathogenic (Aug 17, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919530.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (1) PubMed: 27351199 Comment: Variant summary: IDS c.253G>A (p.Ala85Thr) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of … (more) Variant summary: IDS c.253G>A (p.Ala85Thr) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 169233 control chromosomes (gnomAD). c.253G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome)(Alkhzouz_2016, Amartino_2014, Dvorakova_2017, Kosuga_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Alkhzouz_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Affects (Apr 01, 2014)	no assertion criteria provided Method: research	Mucopolysaccharidosis, MPS-II (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Pediatrics, All India Institute of Medical Sciences, New Delhi Accession: SCV001573770.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Comment: The change c.253G>A, (p.A85T) was found to be a known missense variant, where the non-polar amino acid Alanine at 85 position was substituted with another … (more) The change c.253G>A, (p.A85T) was found to be a known missense variant, where the non-polar amino acid Alanine at 85 position was substituted with another polar amino acid Threonine. Uttarilli et al., described it in MPS II patients with attenuated phenotype from Kerala and Karnataka (Uttarilli et al.,2016). Rathmann et al., described A85T initially in one European MPS-II patients with attenuated phenotype (Rathmann et al.,1982). In our study, it was detected in the hemizygous condition in patients with MPS-II attenuated phenotype, hails from from the state of UP and Bihar, India. (less) Number of individuals with the variant: 3 Clinical Features: Coarse facial features (present) , Arthropathy (present) , Macrocephaly (present) , Hernia (present) , Hepatosplenomegaly (present) , Abnormal echocardiogram (present) Age: 5-12 years Sex: male Ethnicity/Population group: INDIAN Geographic origin: North India (UP & Bihar) Comment on evidence: The change c.253G>A, (p.A85T) was found to be a known missense variant, where the non-polar amino acid Alanine at 85 position was substituted with another … (more) The change c.253G>A, (p.A85T) was found to be a known missense variant, where the non-polar amino acid Alanine at 85 position was substituted with another polar amino acid Threonine. Uttarilli et al., described it in MPS II patients with attenuated phenotype from Kerala and Karnataka (Uttarilli et al.,2016). Rathmann et al., described A85T initially in one European MPS-II patients with attenuated phenotype (Rathmann et al.,1982). In our study, it was detected in the hemizygous condition in two non-familial MPS-II patients from UP and Bihar. (less) Method: Sanger sequencing was performed on ABI 3130 genetic analyser (Applied Biosystem, USA) capillary electrophoresis. Data was analysed by ABI sequence analysis (SeqScape version 2.5) software as well as manually by using software: Chromaspro (Version-1.7.5, Technilysium Pvt. Ltd, Australia) and FinchTV (Version 1.4.0, Geospiza, Perkinelmer, USA).
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Comment:

ClinVar contains an entry for this variant (Variation ID: 92617). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IDS function (PMID: 17091340). 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) performed at Invitae indicates that this missense variant is expected to disrupt IDS protein function. This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 8940265, 25976201, 26762690, 31877959). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 85 of the IDS protein (p.Ala85Thr).

Comment:

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), 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)

Comment:

Variant summary: IDS c.253G>A (p.Ala85Thr) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 169233 control chromosomes (gnomAD). c.253G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome)(Alkhzouz_2016, Amartino_2014, Dvorakova_2017, Kosuga_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Alkhzouz_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The change c.253G>A, (p.A85T) was found to be a known missense variant, where the non-polar amino acid Alanine at 85 position was substituted with another polar amino acid Threonine. Uttarilli et al., described it in MPS II patients with attenuated phenotype from Kerala and Karnataka (Uttarilli et al.,2016). Rathmann et al., described A85T initially in one European MPS-II patients with attenuated phenotype (Rathmann et al.,1982). In our study, it was detected in the hemizygous condition in patients with MPS-II attenuated phenotype, hails from from the state of UP and Bihar, India.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
variation affecting protein (VariO:0002)	Sanger sequencing was performed on ABI 3130 genetic analyser (Applied Biosystem, USA) capillary electrophoresis. Data was analysed by ABI sequence analysis (SeqScape version 2.5) software as well as manually by using software: Chromaspro (Version-1.7.5, Technilysium Pvt. Ltd, Australia) and FinchTV (Version 1.4.0, Geospiza, Perkinelmer, USA).	Result not provided	Pediatrics, All India Institute of Medical Sciences, New Delhi Accession: SCV001573770.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical characteristics and genotypes of 201 patients with mucopolysaccharidosis type II in China: A retrospective, observational study.	Zhong L	Clinical genetics	2023	PMID: 36945845
Genotype-phenotype spectrum of 130 unrelated Indian families with Mucopolysaccharidosis type II.	Agrawal N	European journal of medical genetics	2022	PMID: 35144014
Genotype-phenotype studies in a large cohort of Brazilian patients with Hunter syndrome.	Josahkian JA	American journal of medical genetics. Part C, Seminars in medical genetics	2021	PMID: 33960103
Analysis of long-term observations of the large group of Russian patients with Hunter syndrome (mucopolysaccharidosis type II).	Semyachkina AN	BMC medical genomics	2021	PMID: 33676511
Identification and Functional Characterization of IDS Gene Mutations Underlying Taiwanese Hunter Syndrome (Mucopolysaccharidosis Type II).	Lin HY	International journal of molecular sciences	2019	PMID: 31877959
Genotype-phenotype correlation in 44 Czech, Slovak, Croatian and Serbian patients with mucopolysaccharidosis type II.	Dvorakova L	Clinical genetics	2017	PMID: 27883178
Clinical and Genetic Characteristics of Romanian Patients with Mucopolysaccharidosis Type II.	Alkhzouz C	JIMD reports	2017	PMID: 27351199
Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase.	Kosuga M	Molecular genetics and metabolism	2016	PMID: 27246110
Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with mucopolysaccharidoses type I and type II.	Uttarilli A	Clinical genetics	2016	PMID: 27146977
Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome.	Alcántara-Ortigoza MA	Clinical genetics	2016	PMID: 26762690
Hunter syndrome with late age of presentation: clinical description of a case and review of the literature.	Gupta A	BMJ case reports	2015	PMID: 25976201
Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome).	Amartino H	Molecular genetics and metabolism reports	2014	DOI: 10.1016/j.ymgmr.2014.08.006
Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome).	Amartino H	Molecular genetics and metabolism reports	2014	PMID: 27896113
Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.	Brusius-Facchin AC	Molecular genetics and metabolism	2014	PMID: 24125893
Identification of 11 novel mutations in 49 Korean patients with mucopolysaccharidosis type II.	Sohn YB	Clinical genetics	2012	PMID: 21291454
Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate-2-sulfatase: enzymatic activity, protein processing and structural analysis.	Sukegawa-Hayasaka K	Journal of inherited metabolic disease	2006	PMID: 17091340
Expression studies of mutations underlying Taiwanese Hunter syndrome (mucopolysaccharidosis type II).	Chang JH	Human genetics	2005	PMID: 15614569
Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome).	Li P	Journal of medical genetics	1999	PMID: 9950361
Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients.	Froissart R	Clinical genetics	1998	PMID: 9660053
Mutation analysis in the iduronate-2-sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease).	Isogai K	Journal of inherited metabolic disease	1998	PMID: 9501270
Mutations in the iduronate-2-sulfatase gene in 12 Spanish patients with Hunter disease.	Gort L	Human mutation	1998	PMID: 9452044
Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene.	Rathmann M	American journal of human genetics	1996	PMID: 8940265
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDS	-	-	-	-
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Text-mined citations for rs113993949 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000202.8(IDS):c.253G>A (p.Ala85Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113993949 ...