NM_000203.5(IDUA):c.53T>C (p.Leu18Pro) AND Mucopolysaccharidosis type 1

Clinical significance:Pathogenic (Last evaluated: Aug 26, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001248919.2

Allele description [Variation Report for NM_000203.5(IDUA):c.53T>C (p.Leu18Pro)]

NM_000203.5(IDUA):c.53T>C (p.Leu18Pro)

Genes:
IDUA:alpha-L-iduronidase [Gene - OMIM - HGNC]
SLC26A1:solute carrier family 26 member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4p16.3
Genomic location:
Preferred name:
NM_000203.5(IDUA):c.53T>C (p.Leu18Pro)
HGVS:
  • NC_000004.12:g.987137T>C
  • NG_008103.1:g.5141T>C
  • NG_033042.1:g.11300A>G
  • NM_000203.5:c.53T>CMANE SELECT
  • NM_134425.3:c.576+3991A>G
  • NP_000194.2:p.Leu18Pro
  • LRG_1277t1:c.53T>C
  • LRG_1277:g.5141T>C
  • LRG_1277p1:p.Leu18Pro
  • NC_000004.11:g.980925T>C
  • NM_000203.3:c.53T>C
  • NM_000203.4(IDUA):c.53T>C
  • NR_110313.1:n.141T>C
  • P35475:p.Leu18Pro
Protein change:
L18P
Links:
UniProtKB: P35475#VAR_072367; dbSNP: rs794726878
NCBI 1000 Genomes Browser:
rs794726878
Molecular consequence:
  • NM_134425.3:c.576+3991A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000203.5:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_110313.1:n.141T>C - 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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001422681Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 13, 2020)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001587516Invitaecriteria provided, single submitter
Pathogenic
(Aug 26, 2020)
germlineclinical testing

PubMed (4)
[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

Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses.

Utz JR, Crutcher T, Schneider J, Sorgen P, Whitley CB.

Mol Genet Metab. 2015 Feb;114(2):274-80. doi: 10.1016/j.ymgme.2014.11.015. Epub 2014 Dec 6.

PubMed [citation]
PMID:
25557439
PMCID:
PMC4386860

p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients.

Pasqualim G, Ribeiro MG, da Fonseca GG, Szlago M, Schenone A, Lemes A, Rojas MV, Matte U, Giugliani R.

Clin Genet. 2015 Oct;88(4):376-80. doi: 10.1111/cge.12507. Epub 2014 Oct 21.

PubMed [citation]
PMID:
25256405
See all PubMed Citations (4)

Details of each submission

From Broad Institute Rare Disease Group, Broad Institute, SCV001422681.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The p.Leu18Pro variant in IDUA has been reported in 5 individuals with mucopolysaccharidosis, MSP (PMID: 25256405, 25557439) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 2 individuals with MSP increases the likelihood that the p.Leu18Pro variant is pathogenic (VariationID: 11909, 11908; PMID: 25256405, 25557439). The phenotype of individuals homozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 25256405). The p.Leu18Pro variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 25256405). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM1, PM2_supporting, PP4 (Richards 2015).

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

From Invitae, SCV001587516.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces leucine with proline at codon 18 of the IDUA protein (p.Leu18Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 25557439, 25256405, 31194252). ClinVar contains an entry for this variant (Variation ID: 193062). 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: Not Available; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 7, 2021

Support Center