4-1002333-T-G
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000203.5(IDUA):c.1037T>G(p.Leu346Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Consequence
IDUA
NM_000203.5 missense
NM_000203.5 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 6.04
Genes affected
IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 4-1002333-T-G is Pathogenic according to our data. Variant chr4-1002333-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 11927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.1037T>G | p.Leu346Arg | missense_variant | 8/14 | ENST00000514224.2 | NP_000194.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.1037T>G | p.Leu346Arg | missense_variant | 8/14 | 2 | NM_000203.5 | ENSP00000425081.2 | ||
IDUA | ENST00000247933.9 | c.1037T>G | p.Leu346Arg | missense_variant | 8/14 | 1 | ENSP00000247933.4 | |||
IDUA | ENST00000514698.5 | n.1144T>G | non_coding_transcript_exon_variant | 5/11 | 5 | |||||
IDUA | ENST00000652070.1 | n.1093T>G | non_coding_transcript_exon_variant | 7/13 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248330Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134856
GnomAD3 exomes
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GnomAD4 exome Cov.: 35
GnomAD4 exome
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35
GnomAD4 genome Cov.: 34
GnomAD4 genome
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34
ExAC
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1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 14, 2020 | The p.Leu346Arg variant in IDUA has been reported in at least 19 individuals with mucopolysaccharidosis (MPS) (PMID: 10735634, 21480867, 27520059) and has been identified in 0.006% (1/18160) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965033). 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: 11927) as pathogenic by Counsyl and OMIM. In vitro functional studies provide some evidence that the p.Leu346Arg variant may impact protein function (PMID: 10735634). 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 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: 21480867). The presence of this variant in 4 affected homozygotes and in combination with reported pathogenic or likely pathogenic variants in 5 individuals with MPS1 increases the likelihood that the p.Leu346Arg variant is pathogenic (VariationID: 551563, 11921; PMID: 10735634, 21480867, 27520059). 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 the homozygous state and in combination with other pathogenic variants in individuals with MPS, functional studies, and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM2, PP3, PP4 (Richards 2015). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 10, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 346 of the IDUA protein (p.Leu346Arg). This variant is present in population databases (rs121965033, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 10735634, 15521993, 21480867, 21624210, 29801497). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of East Asian ancestry (PMID: 10735634, 15521993, 21480867, 21624210, 29801497). ClinVar contains an entry for this variant (Variation ID: 11927). 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%. Experimental studies have shown that this missense change affects IDUA function (PMID: 10735634). For these reasons, this variant has been classified as Pathogenic. - |
Hurler syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2004 | - - |
Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at