Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000208599 | SCV005619879 | pathogenic | Mucopolysaccharidosis type 1 | 2024-12-06 | reviewed by expert panel | curation | The NM_000203.5:c.46_57del variant results in an inframe deletion of 4 amino acids (p.Ser16_Ala19del) within the lysosomal signal sequence of IDUA (PM4). This variant is named "134del12" in older literature. At least twelve patients with with variant and a diagnosis of mucopolysaccharidosis type 1 have been reported in the literature. This includes four patients with documented laboratory values showing deficiency of IDUA activity in fibroblasts or leukocytes (PMID: 15300847, 21394825, 23786846) one of whom also had documented clinical features consistent with the diagnosis including corneal clouding, joint stiffness, digital contractures, cardiac valve disease, airway obstruction, and developmental delay (PMID: 15300847) (PP4). Four individuals have been reported who are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including two confirmed in trans - c.1750C>T (p.Gln584Ter) (PMID: 12189649) and p.Trp402Ter (PMID: 11735025); and two phase unknown - c.208C>T (p.Gln70Ter) (PMID: 21394825) and c.386-2A>G (PMID: 11735025). In addition, at least two homozygotes have been reported PMID: 7951228, 21394825) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and c.603C>G (p.Tyr201Ter) (PMID: 21394825), c.1189+5G>A (PMID: 21394825); c.1960T>C (p.Ter654ArgextTer*62) (PMID: 21394825), c.1049A>T (p.Asn350Ile) (PMID: 12559846) and c.1598C>G (p.Pro533Arg) (PMID: 15300847). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. When expressed in COS-7 cells, the variant (labeled as "134del12") resulted in 124.6% of normal activity. A 77-kDa precursor protein was observed on Western blot, compared with a major mature 63-kDa form and a minor 77-kDa precursor in cells transfected with wild-type cDNA. These results suggested that the variant prevents correct posttranslational processing and transport to the lysosome (PMID: 12189649) (PS3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006251 (69/1103836 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 92643). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PM4, PP4, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) |
| Fulgent Genetics, |
RCV005031563 | SCV005672368 | pathogenic | Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S | 2024-05-02 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV003390774 | SCV004119512 | pathogenic | IDUA-related disorder | 2022-12-01 | criteria provided, single submitter | clinical testing | The IDUA c.46_57del12 variant is predicted to result in an in-frame deletion (p.Ser16_Ala19del). This variant is also referred to as 134del12 in the literature. This variant has been reported in the homozygous and compound heterozygous states in individuals with biochemically confirmed mucopolysaccharidosis IH, also referred to as Hurler syndrome (Table 1, Bunge et al. 1994. PubMed ID: 7951228; Lee-Chen et al. 2002. PubMed ID: 12189649; Table 4, Gheldof et al. 2018. PubMed ID: 30548430; Table 2, Fang et al. 2021. PubMed ID: 34813777). Experimental studies using patient derived fibroblasts indicate this variant abolishes IDUA activity (Table 1, Oussoren et al. 2013. PubMed ID: 23786846). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-980906-GCGCTCCTGGCCT-G). This variant is interpreted as pathogenic. |
| Neuberg Centre For Genomic Medicine, |
RCV003338408 | SCV004047117 | pathogenic | Mucopolysaccharidosis, MPS-I-S | criteria provided, single submitter | clinical testing | The inframe deletion c.46_57del variant has been reported previously in patient affected with Mucopolysaccharidosis Is (Izumi et. al., 2018) and has also been reported in multiple unrelated individuals affected with MPS I (Bertola et. al., 2011; Yogalingam et. al., 2004; Bunge et. al., 1994). Experimental studies have shown that this variant change results in a IDUA protein that is not cleaved post-translationally, which may prevent its proper localization to the lysosome and interfere with its normal function despite its increased enzymatic activity (Lee-Chen et. al., 2002). The p.Ser16_Ala19del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and has an allele frequency of 0.006415% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This p.Ser16_Ala19del causes deletion of amino acid Serine at position 16 to Alanine at position 19. This variant is not in the repeat region. For these reasons, this variant has been classified as Pathogenic. | |
| Illumina Laboratory Services, |
RCV000208599 | SCV004014671 | pathogenic | Mucopolysaccharidosis type 1 | 2023-04-11 | criteria provided, single submitter | clinical testing | The IDUA c.46_57del (p.Ser16_Ala19del) variant, also referred to as 134del12, is an in-frame deletion of four amino acids at amino acid position 16. The c.46_57del variant has been reported in both a homozygous and compound heterozygous state in multiple individuals with phenotypes consistent with mucopolysaccharidosis type I (PMID: 7951228; PMID: 11735025; PMID: 12189649; PMID: 15300847; PMID: 21480867). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000130 in the European (non-Finnish) population (version 2.1.1). Functional studies conducted in patient cells suggest that this variant results in decreased enzyme activity and may prevent posttranslational processing and transport into the lysosome (PMID: 12189649; PMID: 23786846). Based on the available evidence, the c.46_57del (p.Ser16_Ala19del) variant is classified as pathogenic for mucopolysaccharidosis type I. |
| Pathology and Clinical Laboratory Medicine, |
RCV001824122 | SCV002073852 | pathogenic | Hurler syndrome | criteria provided, single submitter | clinical testing | ||
| Revvity Omics, |
RCV000173083 | SCV002023101 | pathogenic | not provided | 2023-09-26 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000173083 | SCV001773949 | pathogenic | not provided | 2025-03-18 | criteria provided, single submitter | clinical testing | In-frame deletion of 4 of amino acid(s)in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23786846, 15300847, 28604952, 21734815, 25098213, 7951228, 11735025, 21394825, Fenton-Navarro2017[CaseReport], 12189649, 37218880, 34813777, 30548430, 21480867) |
| Labcorp Genetics |
RCV000208599 | SCV000816966 | pathogenic | Mucopolysaccharidosis type 1 | 2024-11-21 | criteria provided, single submitter | clinical testing | This variant, c.46_57del, results in the deletion of 4 amino acid(s) of the IDUA protein (p.Ser16_Ala19del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398123260, gnomAD 0.01%). This variant has been observed in individual(s) with mucopolysacccharidosis (MPS) type I (PMID: 7951228, 12189649, 15300847, 21394825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92643). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects IDUA function (PMID: 12189649). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000208599 | SCV000695973 | pathogenic | Mucopolysaccharidosis type 1 | 2025-03-03 | criteria provided, single submitter | clinical testing | Variant summary: IDUA c.46_57del12 (p.Ser16_Ala19del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. Functional studies in cultured skin fibroblasts from patients compound heterozygous for this variant have indicated that this variant results in IDUA activity that is lower than heterozygous carriers. It has been suggested that although the precursor Ser16_Ala19del IDUA is enzymatically active, this may prevent correct post-translational processing and transport to the lysosome (Lee-Chen_IDUA_J Formos Med Assoc_2002 ). c.46_57del12 has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11735025, 12189649, 21480867, 15300847). ClinVar contains an entry for this variant (Variation ID: 92643). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Eurofins Ntd Llc |
RCV000173083 | SCV000224167 | pathogenic | not provided | 2016-03-22 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000208599 | SCV002083076 | pathogenic | Mucopolysaccharidosis type 1 | 2020-07-24 | no assertion criteria provided | clinical testing |