ClinVar Genomic variation as it relates to human health

A homozygous missense variant in exon 10 of the IDUA gene that results in the amino acid substitution of Proline for Leucine at codon 490 was detected. The observed variant c.1469T>C:p.(Leu490Pro) has not been reported in the 1000 genomes and has a MAF of 0.002% in the ExAC databases. The in silico prediction of the variant is damaging by PROVEAN and MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic.

Variant summary: IDUA c.1469T>C (p.Leu490Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 149530 control chromosomes (gnomAD). c.1469T>C has been reported in the literature in multiple individuals affected with attenuated Hurler Scheie (example: Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Oussorena_2013). The following publications have been ascertained in the context of this evaluation (PMID: 28752568, 23786846). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Leu490Pro variant in IDUA has been reported in at least 20 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 7550232, 11735025, 21394825) and has been Identified in 0.026% (6/22666) of South Asian chromosomes and 0.001% (1/69396) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965027). 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: 11919) as Pathogenic by EGL Genetic Diagnostics, Counsyl, and OMIM. In vitro functional studies provide some evidence that the p.Leu490Pro variant may impact protein function (PMID: 7550232). However, these types of assays may not accurately represent biological function. The phenotype of individuals homozygous for this variant is highly specific for MPS1 based on alpha-l-iduronidase activity being <1% of normal consistent with disease (PMID: 27146977). The presence of this variant in at least 19 affected homozygotes and in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Leu490Pro variant is pathogenic (VariationID: 556406; PMID: 28752568, 7550232, 11735025, 21394825, 27146977). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM2_supporting, PP4 (Richards 2015).

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23786846). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011919). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:11735025, 17570076, 21394825, 27146977, 28752568, 7550232). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:, 21394825, 27146977, 28752568). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Published functional studies demonstrate this variant results in reduced IDUA activity (Tieu et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28752568, 27146977, 21394825, 31400021, 31473686, 31589614, 23786846, 7550232)

The missense variant p.L490P in IDUA (NM_000203.4) has been reported previously in multiple patients in homozygous state including those of Indian origin (Uttarilli A et al,2016). Although the variant is present at 0.0047% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.L490P variant is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between leucine and proline. For these reasons, this variant has been classified as Likely Pathogenic.

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 490 of the IDUA protein (p.Leu490Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 7550232, 21394825, 27146977). ClinVar contains an entry for this variant (Variation ID: 11919). 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. Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232). For these reasons, this variant has been classified as Pathogenic.