Variant: NM_000203.5(IDUA):c.1962A>T (p.Ter654Cys)

CA353725

242721 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: e80fb1cd-2dc1-40d2-85bd-22c72ebc1403

Approved on: 2024-12-05

Published on: 2025-03-18

HGVS expressions

NM_000203.5:c.1962A>T
NM_000203.5(IDUA):c.1962A>T (p.Ter654Cys)
NC_000004.12:g.1004393A>T
CM000666.2:g.1004393A>T
NC_000004.11:g.998181A>T
CM000666.1:g.998181A>T
NC_000004.10:g.988181A>T
NG_008103.1:g.22397A>T
ENST00000247933.9:c.1962A>T
ENST00000514224.2:c.1962A>T
ENST00000652070.1:n.2018A>T
ENST00000247933.8:c.1962A>T
ENST00000514224.1:c.1566A>T
ENST00000514698.5:n.2073A>T
NM_000203.4:c.1962A>T
NR_110313.1:n.2054A>T
NM_001363576.1:c.1566A>T

Likely Pathogenic

• Met criteria codes: PM5_Supporting PS3_Supporting PM4 PM2 PM3_Supporting

• Not Met criteria codes: PP4

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000203.5:c.1962A>T in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Cys), resulting in an increase in the length of the protein (PM1). The variant was identified in homozygosity in a patient with clinical symptoms consistent with MPS 1 and positive urine spot test for GAGs (PM3_Supporting). IDUA activity was deficient. However, because the patient is also homozygous for a benign "pseudodeficiency" variant (c.1225G>C, p.Gly409Arg), there is insufficient data to apply PP4 (PMID: 8328452). When expressed in COS-1 cells, the p.Ter654Cys variant resulted in 2% normal activity (PMID: 8328452) (PS3_Supporting). Three other variants in the stop codon of IDUA have been reported, one of which, c.1960T>C (p.Ter654Arg) (Bertola et al, PMID: 21394825; Ngiwsara et al, PMID: 29282708), has been classified as likely pathogenic by the ClinGen LD VCEP (PM5_Supporting). The other variants are c.1960T>G (p.Ter654Gly) (Tieu et al, 1995, PMID: 7550232), and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762). There is a ClinVar entry for the variant (Variation ID: 242721). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications 1.0.0): PM4, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)

Met criteria codes

• PM5_Supporting: Other IDUA stop loss variants have been reported in patients with MPS 1. One of these variants, c.1960T>C (p.Ter654Arg) (Bertola et al, PMID: 21394825; Ngiwsara et al, PMID: 29282708), has been classified as likely pathogenic by the ClinGen LD VCEP. The other variants are c.1960T>G (p.Ter654Gly) (Tieu et al, 1995, PMID: 7550232), and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762).
• PS3_Supporting: This variant was identified in a patient who is homozygous for the variant and p.Gly409Arg. When expressed in COS-1 cells, either alone or in cis with p.Gly409Arg, the p.Ter654Cys resulted in 2% normal activity. When p.Gly409Arg was expressed alone, the activity was 61% of normal (PMID: 8328452) (PS3_Supporting).
• PM4: The NM_000203.5:c.1962A>T in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Cys), resulting in an increase in the length of the protein (PM1).
• PM2: The variant is not in gnomAD v4.0. (PM2_Supporting).
• PM3_Supporting: One patient is homozygous for the variant and a benign "pseudodeficiency" variant, c.1225G>C (p.Gly409Arg) (PMID: 8328452). 0.5 points (PM3_Supporting)

Not Met criteria codes

• PP4: The variant was identified in a patient with clinical symptoms consistent with MPS 1 and positive urine spot test for GAGs. IDUA activity was deficient. However, because the patient is also homozygous for a pseudodeficiency variant (p.Gly409Arg), there is insufficient data to meet PP4.