NM_000203.5(IDUA):c.1695_1705del (p.Leu566fs) AND Mucopolysaccharidosis type 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 19, 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:: RCV001068754.7

Allele description [Variation Report for NM_000203.5(IDUA):c.1695_1705del (p.Leu566fs)]

NM_000203.5(IDUA):c.1695_1705del (p.Leu566fs)

Gene:

IDUA:alpha-L-iduronidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000203.5(IDUA):c.1695_1705del (p.Leu566fs)

HGVS:

NC_000004.12:g.1003593_1003603del
NG_008103.1:g.21597_21607del
NM_000203.5:c.1695_1705delMANE SELECT
NM_001363576.1:c.1299_1309del
NP_000194.2:p.Leu566fs
NP_001350505.1:p.Leu434fs
LRG_1277t1:c.1695_1705del
LRG_1277:g.21597_21607del
LRG_1277p1:p.Leu566fs
NC_000004.11:g.997376_997386del
NC_000004.11:g.997381_997391del
NM_000203.4:c.1695_1705del
NM_000203.4:c.1695_1705del11
NR_110313.1:n.1783_1793del

Protein change:

L434fs

Links:

dbSNP: rs1220371654

NCBI 1000 Genomes Browser:

rs1220371654

Molecular consequence:

NM_000203.5:c.1695_1705del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363576.1:c.1299_1309del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_110313.1:n.1783_1793del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis type 1 (MPS1)
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
SCV001233886	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7550242, 11735025, 21480867, 28492532
SCV002555650	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001233886

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 19, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002555650

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jun 1, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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 (4)

Details of each submission

From Invitae, SCV001233886.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This premature translational stop signal has been observed in individual(s) with Hurler syndrome (PMID: 7550242). ClinVar contains an entry for this variant (Variation ID: 862097). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu566Glyfs*2) 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).

#	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, SCV002555650.1

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

Description

Variant summary: IDUA c.1695_1705del11 (p.Leu566GlyfsX2) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 242986 control chromosomes (gnomAD). c.1695_1705del11 has been reported in a heterozygous patient with Hurler Syndrome (example: Bunge_1995). This report does not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type 1. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely 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: Feb 20, 2024

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