4-1002087-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000203.5(IDUA):c.898G>A(p.Ala300Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,580,370 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A300A) has been classified as Likely benign.
Frequency
Consequence
NM_000203.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.898G>A | p.Ala300Thr | missense_variant | 7/14 | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.898G>A | p.Ala300Thr | missense_variant | 7/14 | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000840 AC: 12AN: 1428170Hom.: 0 Cov.: 35 AF XY: 0.00000424 AC XY: 3AN XY: 707114
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 300 of the IDUA protein (p.Ala300Thr). 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: 8554071). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11923). 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 80%. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 24, 2021 | - - |
IDUA pseudodeficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 27, 2023 | - - |
Hurler syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at