NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro) AND Mucopolysaccharidosis type 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 4, 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:: RCV001204340.19

Allele description [Variation Report for NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro)]

NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro)

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.1469T>C (p.Leu490Pro)

HGVS:

NC_000004.12:g.1003102T>C
NG_008103.1:g.21106T>C
NM_000203.4(IDUA):c.1469T>C
NM_000203.5:c.1469T>CMANE SELECT
NM_001363576.1:c.1073T>C
NP_000194.2:p.Leu490Pro
NP_000194.2:p.Leu490Pro
NP_001350505.1:p.Leu358Pro
LRG_1277t1:c.1469T>C
LRG_1277:g.21106T>C
LRG_1277p1:p.Leu490Pro
NC_000004.11:g.996890T>C
NM_000203.3:c.1469T>C
NM_000203.4(IDUA):c.1469T>C
NM_000203.4:c.1469T>C
NM_000203.5:c.1469T>C
NR_110313.1:n.1557T>C
P35475:p.Leu490Pro

Protein change:

L358P; LEU490PRO

Links:

UniProtKB: P35475#VAR_003374; OMIM: 252800.0012; dbSNP: rs121965027

NCBI 1000 Genomes Browser:

rs121965027

Molecular consequence:

NM_000203.5:c.1469T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.1073T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.1557T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

Unknown function

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
SCV001375542	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21394825, 27146977, 7550232, 28492532
SCV001422525	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 14, 2020)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 7550232, 27146977, 11735025, 28752568, 21394825, 23786846, 25741868 Citation Link,
SCV002075366	Natera, Inc.	no assertion criteria provided	Pathogenic (Apr 7, 2020)	germline	clinical testing
SCV004037861	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23786846, 28752568 Citation Link

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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

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

Four novel mutations underlying mild or intermediate forms of alpha-L-iduronidase deficiency (MPS IS and MPS IH/S).

Tieu PT, Bach G, Matynia A, Hwang M, Neufeld EF.

Hum Mutat. 1995;6(1):55-9.

PubMed [citation]

PMID:: 7550232

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001375542.5

#	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 490 of the IDUA protein (p.Leu490Pro). 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: 7550232, 21394825, 27146977). ClinVar contains an entry for this variant (Variation ID: 11919). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232). 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, SCV001422525.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

Description

The p.Leu490Pro variant in IDUA has been reported in at least 20 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 7550232, 11735025, 21394825) and has been Identified in 0.026% (6/22666) of South Asian chromosomes and 0.001% (1/69396) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965027). 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: 11919) as Pathogenic by EGL Genetic Diagnostics, Counsyl, and OMIM. In vitro functional studies provide some evidence that the p.Leu490Pro variant may impact protein function (PMID: 7550232). However, these types of assays may not accurately represent biological function. The phenotype of individuals homozygous for this variant is highly specific for MPS1 based on alpha-l-iduronidase activity being <1% of normal consistent with disease (PMID: 27146977). The presence of this variant in at least 19 affected homozygotes and in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Leu490Pro variant is pathogenic (VariationID: 556406; PMID: 28752568, 7550232, 11735025, 21394825, 27146977). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM2_supporting, 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 Natera, Inc., SCV002075366.1

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004037861.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: IDUA c.1469T>C (p.Leu490Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 149530 control chromosomes (gnomAD). c.1469T>C has been reported in the literature in multiple individuals affected with attenuated Hurler Scheie (example: Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Oussorena_2013). The following publications have been ascertained in the context of this evaluation (PMID: 28752568, 23786846). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Nov 10, 2024

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