rs727503967
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000203.5(IDUA):βc.1614delGβ(p.His539fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000091 in 1,538,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000026 ( 0 hom., cov: 33)
Exomes π: 0.0000072 ( 0 hom. )
Consequence
IDUA
NM_000203.5 frameshift
NM_000203.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.130
Genes affected
IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-1003433-TG-T is Pathogenic according to our data. Variant chr4-1003433-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 167191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.0000263 AC: 4AN: 152078Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000145 AC: 2AN: 137732Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 75288
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GnomAD4 exome AF: 0.00000721 AC: 10AN: 1386478Hom.: 0 Cov.: 33 AF XY: 0.00000438 AC XY: 3AN XY: 684778
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GnomAD4 genome 0.0000263 AC: 4AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74296
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 03, 2021 | Variant summary: IDUA c.1614delG (p.His539ThrfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.5e-05 in 137732 control chromosomes. c.1614delG has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (Scott_1993, Vazna_2009). These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | This sequence change creates a premature translational stop signal (p.His539Thrfs*21) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is present in population databases (rs727503967, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 8213840, 19396826). This variant is also known as delG1702. ClinVar contains an entry for this variant (Variation ID: 167191). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.His539ThrfsTer21 variant in IDUA has been reported in at least 2 individuals with mucopolysaccharidosis (MPS) (PMID: 19396826, 8213840) and has been identified in 0.012% (1/8140) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP 167191). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 167191) as pathogenic by EGL Genetic Diagnostics and Counsyl. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 539 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in combination with a reported pathogenic variant in an individual with MPS slightly increases the likelihood that the p.His539ThrfsTer21 variant is pathogenic (VariationID: 11909; VariationID: 8213840). The phenotype of an individual compound heterozygous for this variant is highly specific for MPS based on null alpha-L-iduronidase protein activity, consistent with disease (PMID: 8213840). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it will cause loss of function of the IDUA gene, the presence of the variant in combination with pathogenic variants, and the phenotype of an individual with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2_supporting, PP4 (Richards 2015). - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 29, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 21, 2014 | - - |
Hurler syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 01, 2017 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1993 | - - |
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 29, 2022 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at