rs398123260
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_000203.5(IDUA):βc.46_57delβ(p.Ser16_Ala19del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000505 in 1,445,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Likely benign.
Frequency
Consequence
NM_000203.5 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.46_57del | p.Ser16_Ala19del | inframe_deletion | 1/14 | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.46_57del | p.Ser16_Ala19del | inframe_deletion | 1/14 | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152036Hom.: 0 Cov.: 36
GnomAD4 exome AF: 0.0000495 AC: 64AN: 1293482Hom.: 0 AF XY: 0.0000596 AC XY: 38AN XY: 637434
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152036Hom.: 0 Cov.: 36 AF XY: 0.0000269 AC XY: 2AN XY: 74276
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 30, 2016 | Variant summary: The IDUA c.46_57del12 (Ser16_Ala19del) variant result in an in frame deletion of 4 amino acids that are not located in a known functional domain of Alpha-L-iduronidase. One in silico tool predicts a benign outcome for this variant. Functional studies in cultured skin fibroblasts from patients compound heterozygous for this variant have indicated that this variant results in IDUA activity that is lower than heterozygous carriers. It has been suggested that although the precursor Ser16_Ala19del IDUA is enzymatically active, this may prevent correct post-translational processing and transport to the lysosome (Lee-Chen_J Formos Med Assoc_2002 ). This variant was absent in 6918 control chromosomes, but has been identified in many compound heterozygous MPS1 patients reported in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 24, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This variant, c.46_57del, results in the deletion of 4 amino acid(s) of the IDUA protein (p.Ser16_Ala19del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398123260, gnomAD 0.01%). This variant has been observed in individual(s) with mucopolysacccharidosis (MPS) type I (PMID: 7951228, 12189649, 15300847, 21394825). 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: 92643). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects IDUA function (PMID: 12189649). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 11, 2023 | The IDUA c.46_57del (p.Ser16_Ala19del) variant, also referred to as 134del12, is an in-frame deletion of four amino acids at amino acid position 16. The c.46_57del variant has been reported in both a homozygous and compound heterozygous state in multiple individuals with phenotypes consistent with mucopolysaccharidosis type I (PMID: 7951228; PMID: 11735025; PMID: 12189649; PMID: 15300847; PMID: 21480867). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000130 in the European (non-Finnish) population (version 2.1.1). Functional studies conducted in patient cells suggest that this variant results in decreased enzyme activity and may prevent posttranslational processing and transport into the lysosome (PMID: 12189649; PMID: 23786846). Based on the available evidence, the c.46_57del (p.Ser16_Ala19del) variant is classified as pathogenic for mucopolysaccharidosis type I. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 26, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2019 | In-frame deletion/insertion of 4 amino acids in a non-repeat region predicted to critically alter the protein.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30548430, 21394825, 11735025, 15300847, 21480867, 23786846, 28604952, 12189649, 7951228, 25098213, 21734815) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 22, 2016 | - - |
Mucopolysaccharidosis, MPS-I-S Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The inframe deletion c.46_57del variant has been reported previously in patient affected with Mucopolysaccharidosis Is (Izumi et. al., 2018) and has also been reported in multiple unrelated individuals affected with MPS I (Bertola et. al., 2011; Yogalingam et. al., 2004; Bunge et. al., 1994). Experimental studies have shown that this variant change results in a IDUA protein that is not cleaved post-translationally, which may prevent its proper localization to the lysosome and interfere with its normal function despite its increased enzymatic activity (Lee-Chen et. al., 2002). The p.Ser16_Ala19del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and has an allele frequency of 0.006415% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This p.Ser16_Ala19del causes deletion of amino acid Serine at position 16 to Alanine at position 19. This variant is not in the repeat region. For these reasons, this variant has been classified as Pathogenic. - |
IDUA-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 01, 2022 | The IDUA c.46_57del12 variant is predicted to result in an in-frame deletion (p.Ser16_Ala19del). This variant is also referred to as 134del12 in the literature. This variant has been reported in the homozygous and compound heterozygous states in individuals with biochemically confirmed mucopolysaccharidosis IH, also referred to as Hurler syndrome (Table 1, Bunge et al. 1994. PubMed ID: 7951228; Lee-Chen et al. 2002. PubMed ID: 12189649; Table 4, Gheldof et al. 2018. PubMed ID: 30548430; Table 2, Fang et al. 2021. PubMed ID: 34813777). Experimental studies using patient derived fibroblasts indicate this variant abolishes IDUA activity (Table 1, Oussoren et al. 2013. PubMed ID: 23786846). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-980906-GCGCTCCTGGCCT-G). This variant is interpreted as pathogenic. - |
Hurler syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at