rs148775298
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_000203.5(IDUA):c.246C>G(p.His82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,609,594 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).
Frequency
Consequence
NM_000203.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| IDUA | ENST00000514224.2 | c.246C>G | p.His82Gln | missense_variant | Exon 2 of 14 | 2 | NM_000203.5 | ENSP00000425081.2 | ||
| SLC26A1 | ENST00000398516 | c.*937G>C | 3_prime_UTR_variant | Exon 3 of 3 | 1 | NM_022042.4 | ENSP00000381528.2 |
Frequencies
GnomAD3 genomes 0.00375 AC: 571AN: 152240Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00293 AC: 689AN: 235294Hom.: 1 AF XY: 0.00279 AC XY: 358AN XY: 128216
GnomAD4 exome AF: 0.00522 AC: 7601AN: 1457236Hom.: 31 Cov.: 30 AF XY: 0.00492 AC XY: 3563AN XY: 724634
GnomAD4 genome 0.00375 AC: 572AN: 152358Hom.: 1 Cov.: 33 AF XY: 0.00349 AC XY: 260AN XY: 74514
ClinVar
Submissions by phenotype
not provided Benign:3Other:1
- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
IDUA: PM5, BP4, BS2 -
The IDUA p.His82Gln variant was identified in the literature in individuals with Mucopolysaccharidosis type I (MPS type I) disease (Bravo_2017_28721335, Clarke_2016_27939258,Yogalingam_2004_15300847). The variant was also identified in the following databases: dbSNP (ID: rs148775298) as “with other allele”, ClinVar (1x as benign by Gene Reviews, 1x as likely benign by Prevention Genetics, 1x as uncertain significance by EGL Genetic), Clinvitae (3x by ClinVar). This variant was identified in the 1000 Genomes Project in 6 of 5008 chromosomes (frequency: 0.0012), The NHLBI GO Exome Sequencing Project in 63 of 8578 European American alleles (freq. 0.007) and in 5 of 4383 of African American alleles (freq. 0.001), the Exome Aggregation Consortium database (August 8th 2016) in 293 (1 homozygous) of 80272 chromosomes (freq. 0.0036) and the genome Aggregation Database (beta, October 19th 2016) in 766 (2 homozygous) of 261890 chromosomes (freq. 0.003) in the following populations: African in 18 of 22820 chromosomes (freq. 0.0008), other in 16 of 6160 chromosomes (freq. 0.0025), Latino in 118 of 33784 chromosomes (freq. 0.003), European non Finnish in 569 of 116766 chromosomes (freq. 0.005), and Finnish in 45 of 24302 chromosomes (freq. 0.0018), but was not seen in Ashkenazi Jewish, East Asian and South Asian populations, increasing the likelihood this could be a low frequency variant. Lysosomal storage diseases (LSDs) are genetic disorders with an estimated overall prevalence of 1 in 7,700 live births. They are mainly caused by monogenic defects in genes encoding lysosomal enzymes that degrade macromolecules such as glycolipids, glycoproteins and mucopolysaccharides. These defects produce an abnormal and progressive lysosomal accumulation of specific substrates, leading to structural changes and deterioration of the cellular function. LSDs are clinically heterogeneous, being usually undetectable at birth, and characterized by progressive manifestations that may include different organs and systems in the body (Bravo_2017_28721335). A functional study on the level of protein synthesis, stability and specific activity of p.His82Gln variant has determined the nonpathogenic nature of this variant in a Mucopolysaccharidosis Type I patient (Yogalingam_2004_15300847). IDUA pseudodeficiency alleles can result in decreased enzyme activity when found in the homozygous state or in the compound heterozygous state with another pseudodeficiency allele, a pathogenic variant, or a variant of unknown significance. The Missouri NBS program reported that of 46 infants with a positive NBS screen, 26 had leukocyte IDUA enzyme activity below normal levels but above levels identified in patients with confirmed severe MPS I.36 Follow up testing showed that uGAG levels in these infants were not indicative of severe MPS I, and no patient was homozygous or compound heterozygous for previously reported pathogenic variants. Four purported pseudodeficiency missense IDUA alleles were identified (p.A79T, p.H82Q, p.D223N, and p.V322E) of which p.A79T was prevalent in the African American population (Clarke_2016_27939258). The p.His82Gln residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as li -
This variant is associated with the following publications: (PMID: 27939258, 15300847, 23465405, 28721335, 33195954) -
Mucopolysaccharidosis type 1 Uncertain:1Other:2
- pseudodeficiency allele
Pseudodeficiency variants -
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. -
not specified Benign:2
- -
Variant summary: The IDUA c.246C>G (p.His82Gln) variant involves the alteration of a non-conserved nucleotide that is not located within a known functional domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 766/261890 control chromosomes (gnomAD), including 2 homozygotes, at a frequency of 0.0029249, which is approximately equal to the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). In addition, the frequency in the European (Non-Finnish) subpopulation, which includes the two homozygotes, is nearly 2 times higher than the estimated maximal allele frequency (0.00487), suggesting this variant may be a benign polymorphism. The variant has been identified in compound heterozygosity with other variants of possible pathogenicity in patients with an equivocal diagnosis of pseudodeficient MPS1, but patient clinical data and phase of the variants were not reported (Yogalingam_2004). In another published abstract, this variant was not found to segregate with disease in a MPS1 proband with 2 other causative mutation (Johnson_2007). The unaffected father and sister with severely reduced IDUA activity levels, were found to be obligate carriers who harbored this variant in compound heterozygosity with each of probands causative variants, thereby confirming the phase. The variant was found in the homozygous state via newborn screening where the enzyme activity level in a dried blood spot was borderline normal, suggesting the variant may be a pseudodeficiency allele (Scott_2013). A functional study in CHO cells suggests that while there is a reduction in enzyme activity using a fluorimetric substrate, the reduction would not be severe enough to be associated with a disease-causing mutation (Yogalingam_2004). Although the levels of enzyme activity when analyzed using a radiolabelled naturally derived disaccharide substrate were not reported in this study, all literature reports this variant as a pseudodeficiency allele. Another study showed a mild reduction in activity in leukocytes of a suspected MPS I patient with genotype c.246C>G/c.251G>C, but with normal urinary glycosaminoglycan (GAG) levels, suggesting the observed reduction in activity is not sufficient to impair GAG metabolism and cause disease (Bravo_2017). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign, benign, or as clinically benign but reported as a pseudodeficiency allele. Taken together, this variant is classified as Benign. -
Hurler syndrome Benign:1Other:1
- -
- Pseudo-deficiency
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at