ClinVar Genomic variation as it relates to human health
NM_000202.8(IDS):c.257C>T (p.Pro86Leu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000202.8(IDS):c.257C>T (p.Pro86Leu)
Variation ID: 527322 Accession: VCV000527322.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 149503473 (GRCh38) [ NCBI UCSC ] X: 148585003 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 28, 2018 Oct 20, 2024 Jun 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000202.8:c.257C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000193.1:p.Pro86Leu missense NM_001166550.4:c.15-28C>T intron variant NM_006123.5:c.257C>T NP_006114.1:p.Pro86Leu missense NR_104128.2:n.426C>T non-coding transcript variant NC_000023.11:g.149503473G>A NC_000023.10:g.148585003G>A NG_011900.3:g.6862C>T - Protein change
- P86L
- Other names
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- Canonical SPDI
- NC_000023.11:149503472:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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IDS | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
663 | 1580 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2024 | RCV000632180.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 5, 2018 | RCV002458004.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2024 | RCV004584776.4 |
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
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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. |
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Pathogenic
(Jun 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-II
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003825323.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-II
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000753285.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects IDS function (PMID: 9573369, 26407519). 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. ClinVar contains an entry for this variant (Variation ID: 527322). This missense change has been observed in individual(s) with mucopolysaccharidosis (MPS) type II (PMID: 7728156, 9573369, 10215411, 17063374, 22976768, 24515576, 28077157). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the IDS protein (p.Pro86Leu). (less)
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Pathogenic
(Jun 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002739598.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P86L pathogenic mutation (also known as c.257C>T), located in coding exon 3 of the IDS gene, results from a C to T substitution at … (more)
The p.P86L pathogenic mutation (also known as c.257C>T), located in coding exon 3 of the IDS gene, results from a C to T substitution at nucleotide position 257. The proline at codon 86 is replaced by leucine, an amino acid with a few similar properties. This mutation has been detected in several individuals with Mucopolysaccharidosis type II (MPS II; also called Hunter syndrome) (Popowska E, et al. Hum. Mutat. 1995;5(1):97-100; Vafiadaki E, et al. Arch. Dis. Child. 1998 79(3):237-41; Isogai K, et al. J. Inherit. Metab. Dis. 1998;21(1):60-70; Lampe C et al. JIMD Rep, 2014 Mar;14:99-113; Kosuga M et al. Mol. Genet. Metab., 2016 07;118:190-7), and occurred de novo in at least one individual (Chiong MA et al. Orphanet J Rare Dis, 2017 01;12:7). In addition, several functional studies have shown that this mutation disrupts splicing, resulting in a truncated mRNA product which causes a decrease in IDS enzymatic activity and lysosomal formation (Isogai K, et al. J. Inherit. Metab. Dis. 1998;21(1):60-70; Sukegawa-Hayasaka K, et al. J. Inherit. Metab. Dis. 2006 Dec; 29(6):755-61; Matos L et al. Biochim. Biophys. Acta, 2015 Dec;1852:2712-21; Millat G et al. Biochim. Biophys. Acta, 1998 Mar;1406:214-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 07, 2024)
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criteria provided, single submitter
Method: literature only
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Mucopolysaccharidosis, MPS-II
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV005088939.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
Comment:
Classification method: ACMG Guidelines [PMID:25741868] with modifications
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Comment:
In vitro or in vivo functional studies supportive of a damaging effect (PS3_Strong), 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_Strong), 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) (less)
Number of individuals with the variant: 33
Sex: male
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Pathogenic
(Jun 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV005074893.4
First in ClinVar: Jul 15, 2024 Last updated: Oct 20, 2024 |
Comment:
IDS: PM1, PM2, PM5, PM6, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical characteristics and genotypes of 201 patients with mucopolysaccharidosis type II in China: A retrospective, observational study. | Zhong L | Clinical genetics | 2023 | PMID: 36945845 |
Phenotypic and genetic characteristics of 130 patients with mucopolysaccharidosis type II: A single-center retrospective study in China. | Zhang Z | Frontiers in genetics | 2023 | PMID: 36713083 |
Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis Type II. | Herbst ZM | International journal of neonatal screening | 2022 | PMID: 35225932 |
Molecular analysis and novel variation identification of Chinese pedigrees with mucopolysaccharidosis using targeted next-generation sequencing. | Fang X | Clinica chimica acta; international journal of clinical chemistry | 2022 | PMID: 34813777 |
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 |
Genetic analysis of 63 Chinese patients with mucopolysaccharidosis type II: Functional characterization of seven novel IDS variants. | Zhang W | Clinica chimica acta; international journal of clinical chemistry | 2019 | PMID: 30639582 |
Effectiveness of Early Hematopoietic Stem Cell Transplantation in Preventing Neurocognitive Decline in Mucopolysaccharidosis Type II: A Case Series. | Selvanathan A | JIMD reports | 2018 | PMID: 29671225 |
Genotype-phenotype relationship in mucopolysaccharidosis II: predictive power of IDS variants for the neuronopathic phenotype. | Vollebregt AAM | Developmental medicine and child neurology | 2017 | PMID: 28543354 |
Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome. | Chiong MA | Orphanet journal of rare diseases | 2017 | PMID: 28077157 |
Genotype-phenotype correlation in 44 Czech, Slovak, Croatian and Serbian patients with mucopolysaccharidosis type II. | Dvorakova L | Clinical genetics | 2017 | PMID: 27883178 |
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 |
Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II. | Matos L | Biochimica et biophysica acta | 2015 | PMID: 26407519 |
Genetic analysis of 17 children with Hunter syndrome: identification and functional characterization of four novel mutations in the iduronate-2-sulfatase gene. | Chistiakov DA | Journal of genetics and genomics = Yi chuan xue bao | 2014 | PMID: 24780617 |
Enzyme Replacement Therapy in Mucopolysaccharidosis II Patients Under 1 Year of Age. | Lampe C | JIMD reports | 2014 | PMID: 24515576 |
Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients. | Brusius-Facchin AC | Molecular genetics and metabolism | 2014 | PMID: 24125893 |
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. | Pollard LM | Journal of inherited metabolic disease | 2013 | PMID: 22976768 |
Molecular analysis of the iduronate-2-sulfatase gene in Thai patients with Hunter syndrome. | Keeratichamroen S | Journal of inherited metabolic disease | 2008 | PMID: 18500569 |
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 |
Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations. | Alves S | Journal of inherited metabolic disease | 2006 | PMID: 17063374 |
Detection of four novel mutations in the iduronate-2-sulfatase gene. Mutations in brief no. 123. Online. | Balzano N | Human mutation | 1998 | PMID: 10215411 |
Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease). | Vafiadaki E | Archives of disease in childhood | 1998 | PMID: 9875019 |
Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. | Froissart R | Clinical genetics | 1998 | PMID: 9660053 |
COS cell expression studies of P86L, P86R, P480L and P480Q Hunter's disease-causing mutations. | Millat G | Biochimica et biophysica acta | 1998 | PMID: 9573369 |
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 of the iduronate-2-sulfatase gene in 12 Polish patients with mucopolysaccharidosis type II (Hunter syndrome). | Popowska E | Human mutation | 1995 | PMID: 7728156 |
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Text-mined citations for rs1557340280 ...
HelpRecord last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.