Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000203.5(IDUA):c.536C>T (p.Thr179Met)

CA2801986

1455223 (ClinVar)

Gene: IDUA
Condition: mucopolysaccharidosis type 1
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 0f7c71ac-becf-4524-b8e1-5184f56b8916
Approved on: 2024-12-06
Published on: 2024-12-15

HGVS expressions

NM_000203.5:c.536C>T
NM_000203.5(IDUA):c.536C>T (p.Thr179Met)
NC_000004.12:g.1001510C>T
CM000666.2:g.1001510C>T
NC_000004.11:g.995298C>T
CM000666.1:g.995298C>T
NC_000004.10:g.985298C>T
NG_008103.1:g.19514C>T
ENST00000247933.9:c.536C>T
ENST00000514224.2:c.536C>T
ENST00000652070.1:n.592C>T
ENST00000247933.8:c.536C>T
ENST00000502910.5:c.395C>T
ENST00000504568.5:c.496C>T
ENST00000509948.5:c.329C>T
ENST00000514192.5:c.353C>T
ENST00000514224.1:c.140C>T
ENST00000514698.5:n.436C>T
NM_000203.4:c.536C>T
NR_110313.1:n.624C>T
NM_001363576.1:c.140C>T
More

Likely Pathogenic

Met criteria codes 3
PP3_Moderate PM3 PP4_Moderate
Not Met criteria codes 2
PM5 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IDUA Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000203.5:c.536C>T variant in IDUA is predicted to result in a missense substitution, p.Thr179Met. One patient is compound heterozyous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A or (p.Trp402Ter); the variants were identified by trio exome sequencing are are confirmed to be in trans (PMID: 32670797) (PM3). This patient has documented values showing deficient IDUA activity in two independent samples, elevated urine GAGs with high levels of heparan and dermatan sulfate which reduced to only a trace after 12 months of enzyme replacement therapy, and clinical symptoms consistent with the condition (PMID: 32670797) (PP4_Moderate). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.0002 (5/25114 alleles) in the Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion. The next highest population MAF is 0.00003 (4/128740 alleles) in the European non-Finnish population (PM2_Supporting). Other missense variants at the same position have been reported in individuals with MPS1, including c.536C>G (p.Thr179Arg) (PMID: 21480867), and p.Thr179Lys (PMID: 28752568). The classification of c.536C>T (p.Thr179Met) will be used in the assessment of the other variants at Thr179 and is not included here to avoid circular logic. There is a ClinVar entry for this variant (ClinVar ID: 1455223). In summary, this variant meets the criteria to be classified as likely pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3, PP3_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)
Met criteria codes
PP3_Moderate
The computational predictor REVEL gives a score of 0.844 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate).
PM3
One patient is compound heterozyous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A or (p.Trp402Ter); the variants were identified by trio exome sequencing are are confirmed to be in trans (PMID: 32670797). 1 point (PM3).
PP4_Moderate
At least two individuals with this variant have been identified including one, identified by trio whole exome sequencing, with documented values showing deficient IDUA activity in two samples, elevated urine GAGs with high levels of heparan and dermatan sulfate which reduced to only a trace after 12 months of enzyme replacement therapy, and clinical symptoms consistent with the condition (PMID: 32670797) (PP4_Moderate).
Not Met criteria codes
PM5
Other missense variants at the same position have been reported in individuals with MPS1, including c.536C>G (p.Thr179Arg) (PMID: 21480867), and p.Thr179Lys (PMID: 28752568). The classification of c.536C>T (p.Thr179Met) will be used in the assessment of the other variants at Thr179 and is not included here to avoid circular logic.
PM2
The highest population minor allele frequency (MAF) in gnomAD v4.1.0. is 0.0003482 (22/63178 alleles; no homozygotes) in the Finnish population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), not meeting this criterion. The next highest population MAF is 0.00002627 (31/1179960 alleles; no homozygotes) in the European non-Finnish population.
Curation History
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