NM_000203.5(IDUA):c.164dup (p.Leu56fs) AND Mucopolysaccharidosis type 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001060767.8

Allele description [Variation Report for NM_000203.5(IDUA):c.164dup (p.Leu56fs)]

NM_000203.5(IDUA):c.164dup (p.Leu56fs)

Genes:

IDUA:alpha-L-iduronidase [Gene - OMIM - HGNC]
SLC26A1:solute carrier family 26 member 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000203.5(IDUA):c.164dup (p.Leu56fs)

HGVS:

NC_000004.12:g.987814dup
NG_008103.1:g.5818dup
NG_033042.1:g.10628dup
NM_000203.5:c.164dupMANE SELECT
NM_022042.4:c.*1024dupMANE SELECT
NM_134425.4:c.576+3319dup
NM_213613.4:c.*1024dup
NP_000194.2:p.Leu56fs
LRG_1277t1:c.164dup
LRG_1277:g.5818dup
LRG_1277p1:p.Leu56fs
NC_000004.11:g.981596_981597insC
NC_000004.11:g.981602dup
NM_000203.4:c.164dup
NM_000203.4:c.164dupC
NM_000203.5:c.164dupCMANE SELECT
NR_110313.1:n.252dup

Protein change:

L56fs

Links:

dbSNP: rs727503966

NCBI 1000 Genomes Browser:

rs727503966

Molecular consequence:

NM_022042.4:c.*1024dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_213613.4:c.*1024dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000203.5:c.164dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_134425.4:c.576+3319dup - intron variant - [Sequence Ontology: SO:0001627]
NR_110313.1:n.252dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis type 1
Synonyms:: Mucopolysaccharidosis type I; MPS 1; Attenuated MPS I (subtype); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0001586; MedGen: C0023786

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001225478	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 11, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11735025, 21480867, 7550242, 21176924, 28492532
SCV001461746	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001748803	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 2, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7550242, 21176924, 30755342 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001225478

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 11, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001461746

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV001748803

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 2, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Meaney CA, Greenland G, Adams V, Vellodi A, Young EP, Winchester BG.

Hum Genet. 2001 Nov;109(5):503-11. Epub 2001 Oct 19.

PubMed [citation]

PMID:: 11735025

Mucopolysaccharidosis I mutations in Chinese patients: identification of 27 novel mutations and 6 cases involving prenatal diagnosis.

Wang X, Zhang W, Shi H, Qiu Z, Meng Y, Yao F, Wei M.

Clin Genet. 2012 May;81(5):443-52. doi: 10.1111/j.1399-0004.2011.01680.x. Epub 2011 May 16. Erratum in: Clin Genet. 2012 May;81(5):501.

PubMed [citation]

PMID:: 21480867

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225478.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Leu56Alafs*7) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with IDUA-related conditions (PMID: 7550242, 21176924). This variant is also known as 252insC. ClinVar contains an entry for this variant (Variation ID: 855487). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001461746.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001748803.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: IDUA c.164dupC (p.Leu56AlafsX7) 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. The variant allele was found at a frequency of 4.1e-06 in 242100 control chromosomes (gnomAD). c.164dupC has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (e.g. Bunge_1995, Furukawa_2011, Yamazaki_2019). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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