NM_000203.5(IDUA):c.1045G>A (p.Asp349Asn) AND Mucopolysaccharidosis type 1

Clinical significance:Likely pathogenic (Last evaluated: May 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001248916.2

Allele description [Variation Report for NM_000203.5(IDUA):c.1045G>A (p.Asp349Asn)]

NM_000203.5(IDUA):c.1045G>A (p.Asp349Asn)

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.1045G>A (p.Asp349Asn)
HGVS:
  • NC_000004.12:g.1002341G>A
  • NG_008103.1:g.20345G>A
  • NM_000203.5:c.1045G>AMANE SELECT
  • NM_001363576.1:c.649G>A
  • NP_000194.2:p.Asp349Asn
  • NP_001350505.1:p.Asp217Asn
  • LRG_1277t1:c.1045G>A
  • LRG_1277:g.20345G>A
  • LRG_1277p1:p.Asp349Asn
  • NC_000004.11:g.996129G>A
  • NM_000203.3:c.1045G>A
  • NM_000203.4(IDUA):c.1045G>A
  • NR_110313.1:n.1133G>A
  • P35475:p.Asp349Asn
Protein change:
D217N
Links:
UniProtKB: P35475#VAR_003362; dbSNP: rs368454909
NCBI 1000 Genomes Browser:
rs368454909
Molecular consequence:
  • NM_000203.5:c.1045G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363576.1:c.649G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_110313.1:n.1133G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001422672Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 14, 2020)
germlinecuration

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

Citation Link,

SCV001576109Invitaecriteria provided, single submitter
Likely pathogenic
(May 20, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Human α-L-iduronidase uses its own N-glycan as a substrate-binding and catalytic module.

Maita N, Tsukimura T, Taniguchi T, Saito S, Ohno K, Taniguchi H, Sakuraba H.

Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14628-33. doi: 10.1073/pnas.1306939110. Epub 2013 Aug 19.

PubMed [citation]
PMID:
23959878
PMCID:
PMC3767532

Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase.

Bie H, Yin J, He X, Kermode AR, Goddard-Borger ED, Withers SG, James MN.

Nat Chem Biol. 2013 Nov;9(11):739-45. doi: 10.1038/nchembio.1357. Epub 2013 Sep 11. Erratum in: Nat Chem Biol. 2013 Nov;9(11):746.

PubMed [citation]
PMID:
24036510
PMCID:
PMC4954775
See all PubMed Citations (8)

Details of each submission

From Broad Institute Rare Disease Group, Broad Institute, SCV001422672.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

The p.Asp349Asn variant in IDUA has been reported in 2 individuals with mucopolysaccharidosis (MPS) (PMID: 1627351, 8680403) and has been identified in 0.006% (1/15972) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368454909). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 92623) as pathogenic by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Asp349Asn variant may impact protein function (PMID: 1627351). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Asp349Asn variant is pathogenic (VariationID: 11909; PMID: 8680403). This variant is located in a region of IDUA that is essential to substrate binding, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24036510, 23959878, 1627351). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PS3_moderate, PP3, PM3_supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001576109.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces aspartic acid with asparagine at codon 349 of the IDUA protein (p.Asp349Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs368454909, ExAC 0.01%). This variant has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8680403, 31194252). ClinVar contains an entry for this variant (Variation ID: 92623). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Asp349 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12203999, 12559846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 16, 2021

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