rs776098539
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000203.5(IDUA):āc.536C>Gā(p.Thr179Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,944 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T179A) 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.536C>G | p.Thr179Arg | missense_variant | 5/14 | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.536C>G | p.Thr179Arg | missense_variant | 5/14 | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460944Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726766
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 10, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 179 of the IDUA protein (p.Thr179Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21480867). ClinVar contains an entry for this variant (Variation ID: 556358). 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%. This variant disrupts the p.Thr179 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been observed in individuals with IDUA-related conditions (PMID: 28752568), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2023 | Variant summary: IDUA c.536C>G (p.Thr179Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250946 control chromosomes (gnomAD). c.536C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucopolysaccharidosis Type 1 (e.g. Wang_2012, Hu_2018, Fang_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34813777, 29095814, 21480867). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at