NM_000203.5(IDUA):c.653T>C (p.Leu218Pro) AND Mucopolysaccharidosis type 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 16, 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:: RCV000208593.14

Allele description [Variation Report for NM_000203.5(IDUA):c.653T>C (p.Leu218Pro)]

NM_000203.5(IDUA):c.653T>C (p.Leu218Pro)

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.653T>C (p.Leu218Pro)

HGVS:

NC_000004.12:g.1001742T>C
NG_008103.1:g.19746T>C
NM_000203.5:c.653T>CMANE SELECT
NM_001363576.1:c.257T>C
NP_000194.2:p.Leu218Pro
NP_001350505.1:p.Leu86Pro
LRG_1277t1:c.653T>C
LRG_1277:g.19746T>C
LRG_1277p1:p.Leu218Pro
NC_000004.11:g.995530T>C
NM_000203.3:c.653T>C
NM_000203.5(IDUA):c.653T>CMANE SELECT
NR_110313.1:n.741T>C
P35475:p.Leu218Pro

Protein change:

L218P

Links:

UniProtKB: P35475#VAR_003358; dbSNP: rs869025584

NCBI 1000 Genomes Browser:

rs869025584

Molecular consequence:

NM_000203.5:c.653T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.257T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.741T>C - 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
SCV001422943	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 13, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 22976768, 7951228, 23837464, 25741868 Citation Link,
SCV001588466	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7951228, 22976768, 23786846, 28492532
SCV002075303	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 21, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422943

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 13, 2020)

germline

curation

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

Citation Link,

SCV001588466

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 16, 2023)

germline

clinical testing

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

SCV002075303

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 21, 2021)

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

An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life.

Kingma SD, Langereis EJ, de Klerk CM, Zoetekouw L, Wagemans T, Ĳlst L, Wanders RJ, Wijburg FA, van Vlies N.

Orphanet J Rare Dis. 2013 Jul 9;8:99. doi: 10.1186/1750-1172-8-99.

PubMed [citation]

PMID:: 23837464
PMCID:: PMC3710214

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (6)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422943.2

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

Description

The p.Leu218Pro variant in IDUA has been reported in at least 15 individuals with mucopolysaccharidosis (MPS) (PMID: 22976768, 23837464, 7951228) and has been identified in 0.002% (2/102072) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs869025584). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The Leu at position 218 is not highly conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. However, additional computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 11 individuals with MPS increases the likelihood that the p.Leu218Pro variant is pathogenic (VariationID: 11908, 11909; PMID: 22976768, 23837464, 7951228). The phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1% of normal, consistent with disease (PMID: 23837464). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based its detection in combination with reported pathogenic variants, its low frequency in the general population, and the phenotype of patients with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4 (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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001588466.4

#	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 proline, which is neutral and non-polar, at codon 218 of the IDUA protein (p.Leu218Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 7951228, 22976768, 23786846). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 222995). 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 80%. 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 Natera, Inc., SCV002075303.1

#	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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