rs779762183
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4PP5_Very_Strong
The NM_000203.5(IDUA):c.878_889dup(p.Thr293_Tyr296dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,594,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000076 ( 0 hom. )
Consequence
IDUA
NM_000203.5 inframe_insertion
NM_000203.5 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.937
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 14 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000203.5
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000203.5.
PP5
?
Variant 4-1002063-G-GACACCCCCATTT is Pathogenic according to our data. Variant chr4-1002063-G-GACACCCCCATTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.878_889dup | p.Thr293_Tyr296dup | inframe_insertion | 7/14 | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.878_889dup | p.Thr293_Tyr296dup | inframe_insertion | 7/14 | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 34
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GnomAD4 exome AF: 0.00000763 AC: 11AN: 1442622Hom.: 0 Cov.: 34 AF XY: 0.00000559 AC XY: 4AN XY: 715726
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 04, 2023 | Variant summary: IDUA c.878_889dup12 (p.Thr293_Tyr296dup) results in an in-frame duplication that is predicted to duplicate 4 amino acids into the encoded protein. The variant allele was found at a frequency of 6.6e-06 in 150926 control chromosomes (gnomAD v3.1.2). c.878_889dup12 has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucopolysaccharidosis Type 1 (e.g. Bunge_1995, Bertola_2011, Chistiakov_2014, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. Residual IDUA activity was 0.9% in cells from a compound heterozygous individual that carried a null variant in trans, indicating this variant also results in loss of function (Oussoren_2013). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 14, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | This variant, c.878_889dup, results in the insertion of 4 amino acid(s) of the IDUA protein (p.Thr293_Tyr296dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with mucopolysaccharidosis (MPS) type I (PMID: 9787109, 12203999, 21394825, 23786846; Invitae). ClinVar contains an entry for this variant (Variation ID: 550382). 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: 11735025). For these reasons, this variant has been classified as Pathogenic. - |
Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 20, 2017 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at