VCV000092622.31 - ClinVar

NM_000202.8(IDS):c.641C>T (p.Thr214Met)

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.

(14)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Benign(6); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000202.8(IDS):c.641C>T (p.Thr214Met)

Variation ID: 92622 Accession: VCV000092622.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 149498174 (GRCh38) [ NCBI UCSC ] X: 148579705 (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.641C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000193.1:p.Thr214Met	missense
NM_000202.4:c.641C>T
NM_000202.7:c.641C>T
NM_001166550.4:c.371C>T	NP_001160022.1:p.Thr124Met	missense
NM_006123.5:c.641C>T	NP_006114.1:p.Thr214Met	missense
NR_104128.2:n.810C>T		non-coding transcript variant
NC_000023.11:g.149498174G>A
NC_000023.10:g.148579705G>A
NG_011900.3:g.12161C>T
NG_042264.1:g.11529G>A

... more HGVS ... less HGVS

Protein change

T214M, T124M

Other names

Canonical SPDI

NC_000023.11:149498173:G:A

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

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.

0.01589 (A)

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

1000 Genomes Project 0.01589

1000 Genomes Project 30x 0.01644

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01742

The Genome Aggregation Database (gnomAD), exomes 0.00398

Exome Aggregation Consortium (ExAC) 0.00506

The Genome Aggregation Database (gnomAD) 0.01492

Trans-Omics for Precision Medicine (TOPMed) 0.01567

Links

ClinGen: CA331784 dbSNP: rs61736892 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
LOC106050102	-	-	-	GRCh38	-	749

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.
not specified	Benign (3)	criteria provided, single submitter	Jul 8, 2014	RCV000078368.16
Mucopolysaccharidosis, MPS-II	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Jun 7, 2024	RCV000205107.29
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	May 5, 2021	RCV000587097.14
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	Jun 27, 2014	RCV002311549.9

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.
Benign (Jul 08, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110214.8 First in ClinVar: Jan 17, 2014 Last updated: Jun 28, 2015	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
Likely benign (Nov 21, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: unknown Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000883117.1 First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016
Benign (Jan 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984322.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Likely benign (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: SCV002014457.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021
Benign (Jun 27, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000846798.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Jun 26, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695964.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (1) PubMed: 21639919 Comment: Variant summary: The IDS c.641C>T (p.Thr214Met) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome for this … (more) Variant summary: The IDS c.641C>T (p.Thr214Met) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 444/87744 control chromosomes (12 homozygotes, 100 hemizygotes) at a frequency of 0.0050602, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic IDS variant (0.0028868), suggesting this variant is likely a benign polymorphism. A publication, Chkioua_2011, cites the variant in an affected individual, who was homozygous for the pathogenic R88P variant. This variant also co-occurred with a pathogenic variant, c.1402C>T (p.R468W) in a sample tested at our laboratory. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. (less)
Benign (May 05, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001949054.2 First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 21605424, 27884173, 27695081, 27896113, 31019283, 32448126)
Pathogenic (Dec 07, 2010)	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: SCV000262525.2 First in ClinVar: Feb 02, 2016 Last updated: Dec 30, 2023	Publications: DOI: 10.1016/j.ymgmr.2014.08.006 DOI: 10.1016/j.ymgmr.2014.08.006 Comment: The patient with this genetic variant is hemizygous for the variant in IDS gene: c.641C>T It is an X-linked disorder The disorder is Hunter disease … (more) The patient with this genetic variant is hemizygous for the variant in IDS gene: c.641C>T It is an X-linked disorder The disorder is Hunter disease or mucopolysaccharidosis type II The patient has a deficient activity of Iduronate 2 sulfatase in dried blood filter paper test. And normal activity of another sulfatase ruling out multiple sulfatase deficiency. He had two other family members affected from the same disorder, from the maternal side: a maternal uncle and maternal grand uncle. Both have died because of Hunter disease. Clinical manifestations are: Cifosis, short neck, disostosis multiplex, coarse face, hernia, macroglosia, claw hand, hepatosplenomegaly (less) Number of individuals with the variant: 1 Sex: male Geographic origin: Argentina
Benign (Jan 31, 2024)	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: SCV001005466.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely 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: SCV005089156.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 Comment: Classification method: ACMG Guidelines [PMID:25741868] with modifications	Publications: PubMed (1) PubMed: 27896113 Comment: 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_Supporting), Missense … (more) 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_Supporting), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate), Multiple lines of computational evidence suggest no impact on gene or gene product (BP4_Supporting) (less) Number of individuals with the variant: 1 Sex: male
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Mucopolysaccharidosis type II Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001462904.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920849.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930394.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800280.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
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Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant summary: The IDS c.641C>T (p.Thr214Met) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 444/87744 control chromosomes (12 homozygotes, 100 hemizygotes) at a frequency of 0.0050602, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic IDS variant (0.0028868), suggesting this variant is likely a benign polymorphism. A publication, Chkioua_2011, cites the variant in an affected individual, who was homozygous for the pathogenic R88P variant. This variant also co-occurred with a pathogenic variant, c.1402C>T (p.R468W) in a sample tested at our laboratory. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign.

Comment:

The patient with this genetic variant is hemizygous for the variant in IDS gene: c.641C>T It is an X-linked disorder The disorder is Hunter disease or mucopolysaccharidosis type II The patient has a deficient activity of Iduronate 2 sulfatase in dried blood filter paper test. And normal activity of another sulfatase ruling out multiple sulfatase deficiency. He had two other family members affected from the same disorder, from the maternal side: a maternal uncle and maternal grand uncle. Both have died because of Hunter disease. Clinical manifestations are: Cifosis, short neck, disostosis multiplex, coarse face, hernia, macroglosia, claw hand, hepatosplenomegaly

Comment:

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_Supporting), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate), Multiple lines of computational evidence suggest no impact on gene or gene product (BP4_Supporting)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients.	Chkioua L	Diagnostic pathology	2011	PMID: 21639919
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDS	-	-	-	-

Text-mined citations for rs61736892 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000202.8(IDS):c.641C>T (p.Thr214Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61736892 ...