4-1002333-T-G

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

Scores

11
7
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.04
Variant links:
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
IDUANM_000203.5 linkuse as main transcriptc.1037T>G p.Leu346Arg missense_variant 8/14 ENST00000514224.2 NP_000194.2 P35475-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IDUAENST00000514224.2 linkuse as main transcriptc.1037T>G p.Leu346Arg missense_variant 8/142 NM_000203.5 ENSP00000425081.2 P35475-1
IDUAENST00000247933.9 linkuse as main transcriptc.1037T>G p.Leu346Arg missense_variant 8/141 ENSP00000247933.4 P35475-1
IDUAENST00000514698.5 linkuse as main transcriptn.1144T>G non_coding_transcript_exon_variant 5/115
IDUAENST00000652070.1 linkuse as main transcriptn.1093T>G non_coding_transcript_exon_variant 7/13

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248330
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000551
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.00000827
AC:
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 submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 14, 2020The 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 providedclinical testingNatera, Inc.Dec 10, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024This 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 submitterclinical testingCounsylNov 02, 2017- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2004- -
Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2004- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.51
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;.
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.6
M;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.3
D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.96
MVP
0.99
MPC
0.91
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.97
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121965033; hg19: chr4-996121; API