NM_000203.5(IDUA):c.713T>A (p.Leu238Gln) AND Mucopolysaccharidosis type 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 30, 2024
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:: RCV000802940.13

Allele description [Variation Report for NM_000203.5(IDUA):c.713T>A (p.Leu238Gln)]

NM_000203.5(IDUA):c.713T>A (p.Leu238Gln)

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.713T>A (p.Leu238Gln)

HGVS:

NC_000004.12:g.1001802T>A
NG_008103.1:g.19806T>A
NM_000203.5:c.713T>AMANE SELECT
NM_001363576.1:c.317T>A
NP_000194.2:p.Leu238Gln
NP_001350505.1:p.Leu106Gln
LRG_1277t1:c.713T>A
LRG_1277:g.19806T>A
LRG_1277p1:p.Leu238Gln
NC_000004.11:g.995590T>A
NM_000203.3:c.713T>A
NM_000203.4:c.713T>A
NM_000203.5(IDUA):c.713T>AMANE SELECT
NR_110313.1:n.801T>A
P35475:p.Leu238Gln

Protein change:

L106Q

Links:

UniProtKB: P35475#VAR_020980; dbSNP: rs148789453

NCBI 1000 Genomes Browser:

rs148789453

Molecular consequence:

NM_000203.5:c.713T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.317T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.801T>A - 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
SCV000942791	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15300847, 21480867, 24368159, 28492532
SCV001422676	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 14, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 24368159, 15300847, 25741868 Citation Link,
SCV001461754	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000942791

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

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

SCV001422676

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 14, 2020)

germline

curation

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

Citation Link,

SCV001461754

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 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, curation

Citations

PubMed

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000942791.6

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 238 of the IDUA protein (p.Leu238Gln). This variant is present in population databases (rs148789453, gnomAD 0.008%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 15300847, 24368159; Invitae). ClinVar contains an entry for this variant (Variation ID: 265418). 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 with a positive predictive value of 95%. This variant disrupts the p.Leu238 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been observed in individuals with IDUA-related conditions (PMID: 21480867, 24368159), which suggests that this may be a clinically significant amino acid residue. 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422676.2

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

Description

The p.Leu238Gln variant in IDUA has been reported in at least 7 individuals with mucopolysaccharidosis (MPS), segregated with disease in 4 affected relatives from 2 families (PMID: 24368159), and has been Identified in 0.014% (2/13914) of African chromosomes and 0.003% (3/102956) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148789453). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Leu238Gln variant may impact protein function (PMID: 15300847). 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 reported pathogenic variants in 5 individuals with MPS increases the likelihood that the p.Leu238Gln variant is pathogenic (VariationID: 11908, 222994; PMID: 24368159). The phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1%, consistent with disease (PMID: 15300847). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with known pathogenic variants, functional studies, cosegregation, and the phenotype of individuals with the variant and MPS being highly specific for IDUA. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PM2_supporting, PP3, PP4, PP1 (Richards 2015).

#	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., SCV001461754.1

#	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: Oct 13, 2024

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