rs752337969
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000203.5(IDUA):āc.923T>Cā(p.Leu308Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000764 in 1,571,548 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). Synonymous variant affecting the same amino acid position (i.e. L308L) 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 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.923T>C | p.Leu308Pro | missense_variant | 7/14 | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.923T>C | p.Leu308Pro | missense_variant | 7/14 | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152138Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000282 AC: 4AN: 1419410Hom.: 0 Cov.: 35 AF XY: 0.00000142 AC XY: 1AN XY: 701992
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74318
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 13, 2020 | The p.Leu308Pro variant in IDUA has been reported in the homozygous state in 2 Mexican individuals with mucopolysaccharidosis (MPS), segregated with disease in 2 affected relatives from 1 family (PMID: 21393040), and has been identified in 0.005% (1/19128) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752337969). 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: 502243) as a VUS by EGL Genetic Diagnostics and Counsyl. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Two affected individuals with this variant were also homozygous for a reported pathogenic variant in another gene known to be associated with another type of MPS (VariationID: 550542). However, these two affected individuals have phenotypes that appear to be consistent with both types of MPS, raising the possibility that this variant is also pathogenic (PMID: 21393040). In summary, the clinical significance of the p.Leu308Pro variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 308 of the IDUA protein (p.Leu308Pro). This variant is present in population databases (rs752337969, gnomAD 0.005%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21393040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 502243). 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. For these reasons, this variant has been classified as Pathogenic. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 29, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 18, 2023 | - - |
Hurler syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at