VCV000011914.7 - ClinVar

NM_000203.5(IDUA):c.192C>A (p.Tyr64Ter)

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.

(5)

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_000203.5(IDUA):c.192C>A (p.Tyr64Ter)

Variation ID: 11914 Accession: VCV000011914.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.3 4: 987842 (GRCh38) [ NCBI UCSC ] 4: 981630 (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	Apr 4, 2013	Feb 14, 2024	Jul 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000203.5:c.192C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000194.2:p.Tyr64Ter	nonsense
NM_022042.4:c.*991G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_000203.4:c.192C>A
NM_134425.4:c.576+3286G>T		intron variant
NM_213613.4:c.*991G>T		3 prime UTR
NR_110313.1:n.280C>A		non-coding transcript variant
NC_000004.12:g.987842C>A
NC_000004.11:g.981630C>A
NG_008103.1:g.5846C>A
NG_033042.1:g.10595G>T
LRG_1277:g.5846C>A
LRG_1277t1:c.192C>A	LRG_1277p1:p.Tyr64Ter

... more HGVS ... less HGVS

Protein change

Y64*

Other names

Canonical SPDI

NC_000004.12:987841:C: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

dbSNP: rs121965022 ClinGen: CA256113 OMIM: 252800.0006 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.
IDUA		-	-	GRCh38 GRCh37	1390	2153
SLC26A1		-	-	GRCh38 GRCh37	3	765

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.
Hurler syndrome	Pathogenic (2)	criteria provided, single submitter	Aug 22, 2017	RCV000012689.14
Mucopolysaccharidosis type 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 19, 2023	RCV001851807.5
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 24, 2022	RCV003137513.3

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 25, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Mucopolysaccharidosis type 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003934353.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (1) PubMed: 8328452 Comment: Variant summary: IDUA c.192C>A (p.Tyr64X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: IDUA c.192C>A (p.Tyr64X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 243844 control chromosomes (gnomAD). c.192C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (example: Bach_1993). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 8328452). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Oct 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003818233.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Aug 22, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Hurler syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000793668.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (3) PubMed: 23430803‚ 8328452‚ 27511503
Pathogenic (Jul 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002241227.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 8328452‚ 11735025‚ 21480867 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. ClinVar contains an entry for this variant (Variation ID: 11914). This premature translational stop signal has been observed in individual(s) with clinical features of mucopolysaccharidosis type I (PMID: 8328452). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr64*) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). (less)
Pathogenic (Aug 01, 1993)	no assertion criteria provided Method: literature only	HURLER SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032924.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (3) PubMed: 6821579‚ 8477267‚ 8328452 Comment on evidence: Schaap and Bach (1980) found 13 Arab patients with Hurler syndrome (607014) but only 1 Jewish patient in Israel where ascertainment of the disorder had … (more) Schaap and Bach (1980) found 13 Arab patients with Hurler syndrome (607014) but only 1 Jewish patient in Israel where ascertainment of the disorder had been complete for 15 years. The mutation in the Jewish patient was the deletion/insertion mutation described by Moskowitz et al. (1993). The Arab patients came from 8 families, 5 of which were Druze and 3 Muslim. Unexpectedly, Bach et al. (1993) found homozygosity for 3 different mutations distributed in 7 families, 5 of them Druze: mutations in exon 2 (tyr64-to-ter), exon 7 (gln310-to-ter; 252800.0007), and exon 8 (thr366-to-pro; 252800.0008). Transfection of mutagenized cDNA into COS-1 cells showed that the missense mutation thr366-to-pro permitted the expression of only trace amounts of alpha-L-iduronidase activity. The nonsense mutations were associated with abnormalities of RNA processing. The tyr64-to-ter mutation was accompanied by a very low level of mRNA and skipping of exon 2. Utilization of a cryptic splice site was observed with the gln310-to-ter mutation. The Druze and Muslim Arab populations have been separated by religion since the inception of the Ismalia or Druze religion in Egypt in the 11th century A.D. At present the Druze live in a defined geographic area of southern Syria, southern Lebanon, and northern Israel; they maintain an isolated social structure with a high rate of consanguineous marriages. The Druze population in Israel numbers about 60,000. Bach et al. (1993) anticipated that MPS in the Druze population would be caused by 1 founder mutation which might or might not be shared with the Muslim patients residing in the surrounding area. They were surprised to find that, in fact, there were 3 different mutations. (less)

Comment:

Variant summary: IDUA c.192C>A (p.Tyr64X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 243844 control chromosomes (gnomAD). c.192C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (example: Bach_1993). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 8328452). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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 variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 11914). This premature translational stop signal has been observed in individual(s) with clinical features of mucopolysaccharidosis type I (PMID: 8328452). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr64*) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867).

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
Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I.	Atçeken N	Turkish journal of medical sciences	2016	PMID: 27511503
Prevalence and Novel Mutations of Lysosomal Storage Disorders in United Arab Emirates : LSD in UAE.	Al-Jasmi FA	JIMD reports	2013	PMID: 23430803
Mucopolysaccharidosis I mutations in Chinese patients: identification of 27 novel mutations and 6 cases involving prenatal diagnosis.	Wang X	Clinical genetics	2012	PMID: 21480867
Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations.	Beesley CE	Human genetics	2001	PMID: 11735025
A deletion/insertion mutation in the IDUA gene in a Libyan Jewish patient with Hurler syndrome (mucopolysaccharidosis IH).	Moskowitz SM	Human mutation	1993	PMID: 8477267
Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area.	Bach G	American journal of human genetics	1993	PMID: 8328452
Incidence of mucopolysaccharidoses in Israel: is Hunter disease a "Jewish disease"?	Schaap T	Human genetics	1980	PMID: 6821579

Text-mined citations for rs121965022 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000203.5(IDUA):c.192C>A (p.Tyr64Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121965022 ...