rs794727239
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM2PP3_StrongBP6
The NM_000203.5(IDUA):āc.245A>Cā(p.His82Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,272 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H82Q) 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 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.245A>C | p.His82Pro | missense_variant | 2/14 | ENST00000514224.2 | |
SLC26A1 | NM_022042.4 | c.*938T>G | 3_prime_UTR_variant | 3/3 | ENST00000398516.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.245A>C | p.His82Pro | missense_variant | 2/14 | 2 | NM_000203.5 | P1 | |
SLC26A1 | ENST00000398516.3 | c.*938T>G | 3_prime_UTR_variant | 3/3 | 1 | NM_022042.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000425 AC: 1AN: 235412Hom.: 0 AF XY: 0.00000779 AC XY: 1AN XY: 128316
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457314Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 724660
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74226
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 82 of the IDUA protein (p.His82Pro). This variant is present in population databases (rs794727239, gnomAD 0.002%). This missense change has been observed in individual(s) with MPS I (PMID: 8401515). ClinVar contains an entry for this variant (Variation ID: 195039). 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) has been performed at Invitae 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 30, 2018 | The IDUA c.245A>C (p.His82Pro) missense variant has been reported in two studies and is found in two individuals in a compound heterozygous state (Clarke and Scott 1993; Venturi et al. 2002). These individuals exhibited an intermediate phenotype characteristic of the Hurler-Scheie syndrome form of mucopolysaccharidosis, type I (MPS I), and also carried a known pathogenic stop-gained variant. The p.His82Pro variant was also reported in a heterozygous state in two additional patients with MPS I in whom a second variant was not identified. The variant was not found in 168 tested control chromosomes. The p.His82Pro variant is reported at a frequency of 0.000017 in the European (non-Finnish) population of the Genome Aggregation Database, though this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, p.His82Pro is classified as a variant is of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Hurler syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 06, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 19, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 19, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at