VCV002436768.4 - ClinVar

NM_000202.8(IDS):c.241C>T (p.Gln81Ter)

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.

(3)

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

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.241C>T (p.Gln81Ter)

Variation ID: 2436768 Accession: VCV002436768.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 149503489 (GRCh38) [ NCBI UCSC ] X: 148585019 (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	Mar 5, 2023	Aug 4, 2024	Jun 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000202.8:c.241C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000193.1:p.Gln81Ter	nonsense
NM_001166550.4:c.15-44C>T		intron variant
NM_006123.5:c.241C>T	NP_006114.1:p.Gln81Ter	nonsense
NR_104128.2:n.410C>T		non-coding transcript variant
NC_000023.11:g.149503489G>A
NC_000023.10:g.148585019G>A
NG_011900.3:g.6846C>T

... more HGVS ... less HGVS

Protein change

Q81*

Other names

Canonical SPDI

NC_000023.11:149503488: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.

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

Links

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 (3)	criteria provided, multiple submitters, no conflicts	Jun 7, 2024	RCV003140688.6

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II (X-linked inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047211.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The IDS c.241C>T variant has been reported in hemizygous state in individuals affected with Mucopolysaccharidosis II (Wraith et. al., 2008). Experimental studies have shown possible … (more) The IDS c.241C>T variant has been reported in hemizygous state in individuals affected with Mucopolysaccharidosis II (Wraith et. al., 2008). Experimental studies have shown possible use of antisense oligonucleotide therapy for redirecting abnormal pre-mRNA splicing in the IDS gene (Liliana et. al., 2015). The c.241C>T variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Delayed speech and language development (present) , Coarse facial features (present) , Flexion contracture (present)
Pathogenic (Jan 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-II Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003825356.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
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: SCV005089666.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 Comment: Classification method: ACMG Guidelines [PMID:25741868] with modifications	Publications: PubMed (1) PubMed: 24125893 Comment: Null variant (PVS1_VeryStrong), In vitro or in vivo functional studies supportive of a damaging effect (PS3_Moderate), Absent from controls (or at low frequency) in gnomAD … (more) Null variant (PVS1_VeryStrong), In vitro or in vivo functional studies supportive of a damaging effect (PS3_Moderate), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) (less) Number of individuals with the variant: 1 Sex: male

Comment:

The IDS c.241C>T variant has been reported in hemizygous state in individuals affected with Mucopolysaccharidosis II (Wraith et. al., 2008). Experimental studies have shown possible use of antisense oligonucleotide therapy for redirecting abnormal pre-mRNA splicing in the IDS gene (Liliana et. al., 2015). The c.241C>T variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

Null variant (PVS1_VeryStrong), In vitro or in vivo functional studies supportive of a damaging effect (PS3_Moderate), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate)

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
Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.	Brusius-Facchin AC	Molecular genetics and metabolism	2014	PMID: 24125893

Text-mined citations for this variant ...

Record last updated Aug 11, 2024

ClinVar Genomic variation as it relates to human health

NM_000202.8(IDS):c.241C>T (p.Gln81Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...