chr4-1004292-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3PM2
This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). This variant is absent in gnomAD v2.0 (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3).There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0): PM2 Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802458/MONDO:0001586/091
Frequency
Consequence
NM_000203.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.1861C>G | p.Arg621Gly | missense_variant | Exon 14 of 14 | 2 | NM_000203.5 | ENSP00000425081.2 | ||
IDUA | ENST00000247933.9 | c.1861C>G | p.Arg621Gly | missense_variant | Exon 14 of 14 | 1 | ENSP00000247933.4 | |||
IDUA | ENST00000514698.5 | n.1972C>G | non_coding_transcript_exon_variant | Exon 11 of 11 | 5 | |||||
IDUA | ENST00000652070.1 | n.1917C>G | non_coding_transcript_exon_variant | Exon 13 of 13 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 151964Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000278 AC: 69AN: 248290Hom.: 1 AF XY: 0.000274 AC XY: 37AN XY: 134874
GnomAD4 exome AF: 0.000206 AC: 301AN: 1458874Hom.: 1 Cov.: 32 AF XY: 0.000204 AC XY: 148AN XY: 725874
GnomAD4 genome AF: 0.000125 AC: 19AN: 151964Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74210
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Uncertain:4
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
The NM_000203.5:c.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). This variant is absent in gnomAD v2.0 (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0): PM2 Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). -
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 621 of the IDUA protein (p.Arg621Gly). This variant is present in population databases (rs121965025, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with IDUA-related conditions. ClinVar contains an entry for this variant (Variation ID: 444626). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:4
PM2 -
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Listed in one table of a publication as being seen heterozygous with unknown phase with a pathogenic variant in a patient with severe MPS I, but is unclear if this may represent a typographical error as this variant is not listed in the other two tables summarizing the identified variants but a nonsense variant at the same nucleotide position is listed (Voskoboeva et al., 2021); Has not otherwise been published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35141277, 34833038, 33301762, 27896125) -
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at