NM_000203.5:c.1893delC
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000203.5(IDUA):c.1893delC(p.Phe632SerfsTer79) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000203.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.1893delC | p.Phe632SerfsTer79 | frameshift_variant | Exon 14 of 14 | 2 | NM_000203.5 | ENSP00000425081.2 | ||
IDUA | ENST00000247933.9 | c.1893delC | p.Phe632SerfsTer68 | frameshift_variant | Exon 14 of 14 | 1 | ENSP00000247933.4 | |||
IDUA | ENST00000514698.5 | n.2004delC | non_coding_transcript_exon_variant | Exon 11 of 11 | 5 | |||||
IDUA | ENST00000652070.1 | n.1949delC | non_coding_transcript_exon_variant | Exon 13 of 13 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459510Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726142
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:3
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IDUA protein in which other variant(s) (p.Ser633Leu) have been determined to be pathogenic (PMID: 11735025, 16438163, 21480867, 26825088, 27146977). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 495733). This frameshift has been observed in individual(s) with Hurler syndrome (PMID: 21394825). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the IDUA gene (p.Phe632Serfs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the IDUA protein and extend the protein by an uncertain number of additional amino acid residues. -
The p.Phe632Serfs variant in IDUA has been reported in at least 2 individuals with mucopolysaccharidosis (MPS) (PMID: 21394825, 29906569) and was absent from large population studies. This variant has been reported in ClinVar (VariationID: 495733) as likely pathogenic by Integrated Genetics. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 632. This termination codon occurs within the the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in an affected homozygote increases the likelihood that the p.Phe632Serfs variant is pathogenic (PMID: 29906569). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2, PM3_supporting (Richards 2015). -
Variant summary: IDUA c.1893delC (p.Phe632SerfsX77+) causes a frameshift which results in an extension of the protein. The variant was absent in 248970 control chromosomes (gnomAD). c.1893delC has been reported in the literature in individuals (compound heterozygous and homozygous) affected with Hurler syndrome - a severe form of Mucopolysaccharidosis Type 1 (Bertola_2011, Oussoren_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Hurler syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at