NM_000203.5(IDUA):c.787A>T (p.Arg263Trp) AND Mucopolysaccharidosis type 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Sep 6, 2022
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:: RCV001153898.12

Allele description [Variation Report for NM_000203.5(IDUA):c.787A>T (p.Arg263Trp)]

NM_000203.5(IDUA):c.787A>T (p.Arg263Trp)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000203.5(IDUA):c.787A>T (p.Arg263Trp)

HGVS:

NC_000004.12:g.1001876A>T
NG_008103.1:g.19880A>T
NM_000203.5:c.787A>TMANE SELECT
NM_001363576.1:c.391A>T
NP_000194.2:p.Arg263Trp
NP_001350505.1:p.Arg131Trp
LRG_1277t1:c.787A>T
LRG_1277:g.19880A>T
LRG_1277p1:p.Arg263Trp
NC_000004.11:g.995664A>T
NM_000203.3:c.787A>T
NM_000203.4:c.787A>T
NR_110313.1:n.875A>T

Protein change:

R131W

Links:

dbSNP: rs201268637

NCBI 1000 Genomes Browser:

rs201268637

Molecular consequence:

NM_000203.5:c.787A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.391A>T - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.875A>T - 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
SCV001315208	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV001417589	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 6, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29143201, 30442156, 28492532
SCV002016349	GeneReviews	no classification provided	not provided	germline	literature only
SCV002075313	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jun 1, 2020)	germline	clinical testing

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, literature only

Citations

PubMed

Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy.

Burlina AB, Polo G, Salviati L, Duro G, Zizzo C, Dardis A, Bembi B, Cazzorla C, Rubert L, Zordan R, Desnick RJ, Burlina AP.

J Inherit Metab Dis. 2018 Mar;41(2):209-219. doi: 10.1007/s10545-017-0098-3. Epub 2017 Nov 15.

PubMed [citation]

PMID:: 29143201

Newborn screening in mucopolysaccharidoses.

Donati MA, Pasquini E, Spada M, Polo G, Burlina A.

Ital J Pediatr. 2018 Nov 16;44(Suppl 2):126. doi: 10.1186/s13052-018-0552-3. Review. Erratum in: Ital J Pediatr. 2019 Jun 11;45(1):71. doi: 10.1186/s13052-019-0665-3.

PubMed [citation]

PMID:: 30442156
PMCID:: PMC6238254

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001315208.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001417589.3

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 263 of the IDUA protein (p.Arg263Trp). This variant is present in population databases (rs201268637, gnomAD 0.05%). This missense change has been observed in individual(s) with a positive newborn screening result for IDUA-related disease (PMID: 29143201, 30442156). ClinVar contains an entry for this variant (Variation ID: 550605). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 GeneReviews, SCV002016349.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

Description

Pseudodeficiency variants

#	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., SCV002075313.1

#	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

Last Updated: Sep 29, 2024

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