rs758452450
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000203.5(IDUA):c.223G>A(p.Ala75Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,611,924 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 (★★).
Frequency
Consequence
NM_000203.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.223G>A | p.Ala75Thr | missense_variant | Exon 2 of 14 | 2 | NM_000203.5 | ENSP00000425081.2 | ||
SLC26A1 | ENST00000398516 | c.*960C>T | 3_prime_UTR_variant | Exon 3 of 3 | 1 | NM_022042.4 | ENSP00000381528.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000827 AC: 2AN: 241700Hom.: 0 AF XY: 0.00000759 AC XY: 1AN XY: 131768
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459778Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 726154
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74304
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:4
The p.Ala75Thr variant in IDUA has been reported in at least 9 individuals with mucopolysaccharidosis (MPS) (PMID: 29843745, 27146977, 28752568) and has been identified in 0.002% (3/121916) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs758452450). 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 also been reported in ClinVar (VariationID: 222993) as pathogenic by Counsyl and GeneReviews. 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 homozygous and compound heterozygous for this variant is highly specific for MPS based on null alpha-L-iduronidase activity, consistent with disease (PMID: 27146977). The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic and likely pathogenic variants in 5 individuals with MPS increases the likelihood that the p.Ala75Thr variant is pathogenic (VariationID: 11908, 11909; PMID: 29843745, 27146977, 28752568). 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 combination with other pathogenic or likely pathogenic variants in individuals with MPS and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015). -
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 75 of the IDUA protein (p.Ala75Thr). 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: 8680403, 11735025, 16438163, 27146977, 29843745). 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: 222993). Invitae Evidence 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 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. -
Variant summary: IDUA c.223G>A (p.Ala75Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase domain (IPR000514) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241700 control chromosomes. c.223G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (example, Clarke_1994, 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, Tieu_1995). Four clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
not provided Pathogenic:1
- -
Hurler syndrome Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at