rs121965029
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000203.5(IDUA):c.266G>A(p.Arg89Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,600,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000203.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.266G>A | p.Arg89Gln | missense_variant | 2/14 | ENST00000514224.2 | |
SLC26A1 | NM_022042.4 | c.*917C>T | 3_prime_UTR_variant | 3/3 | ENST00000398516.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.266G>A | p.Arg89Gln | missense_variant | 2/14 | 2 | NM_000203.5 | P1 | |
SLC26A1 | ENST00000398516.3 | c.*917C>T | 3_prime_UTR_variant | 3/3 | 1 | NM_022042.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000916 AC: 2AN: 218452Hom.: 0 AF XY: 0.00000841 AC XY: 1AN XY: 118898
GnomAD4 exome AF: 0.0000131 AC: 19AN: 1448664Hom.: 0 Cov.: 30 AF XY: 0.0000167 AC XY: 12AN XY: 719582
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 13, 2020 | The p.Arg89Gln variant in IDUA has been reported in at least 13 individuals with mucopolysaccharidosis (MPS), segregated with disease in 5 affected relatives from 2 families (PMID: 8213840, 8664897, 14559116, 28752568, 11735025, 21480867, and has been identified in 0.006% (1/16554) of East Asian chromosomes and 0.001% (1/94316) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965029). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has been reported pathogenic in ClinVar by Integrated Genetics, OMIM, and GeneReviews (VariationID: 26961). In vitro functional studies provide some evidence that the p.Arg89Gln variant may impact protein function based on reduced protein levels in cells transfected with the variant (PMID: 14559116). However, these types of assays may not accurately represent biological function. The presence of this variant in 4 affected homozygotes and in combination with at least 1 reported pathogenic variant and in 2 individuals with MPS increases the likelihood that the p.Arg89Gln variant is pathogenic (VariationID: 11908; PMID: 8213840, 8664897, 14559116, 28752568). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for MPS based on significantly reduced alpha-L-iduronidase activity levels consistent with disease (PMID: 14559116). The p.Arg89Gln is located in the active site of IDUA, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 14559116, 15862278). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on multiple occurrences with pathogenic IDUA variants in individuals with MPS, in vitro functional studies, and low prevalence of the variant in the population. ACMG/AMP Criteria applied: PM3_strong, PM2, PM1, PS3_moderate, PP3, PM5_supporting, PP4, PP1 (Richards 2015). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Feb 22, 2021 | Common pathogenic variant in Japan; causes attenuated MPS I. May change ability of α-L-iduronidase to affect catalysis. Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 89 of the IDUA protein (p.Arg89Gln). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 11922). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8680403, 21462124, 29282708). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2018 | Variant summary: IDUA c.266G>A (p.Arg89Gln) results in a conservative amino acid change located in the Glycoside hydrolase superfamily of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 62804 control chromosomes (ExAC). The variant, c.266G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1. 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. A reputable database, GeneReviews classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
Hurler syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at