Variant: NM_000203.4(IDUA):c.1960T>G (p.Ter654Gly)

CA256121

11920 (ClinVar)

Gene: N/A

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: 8c66cc97-acc4-4d04-8e83-45a0ba5a18d9

Approved on: 2024-12-06

Published on: 2024-12-16

HGVS expressions

NM_000203.4(IDUA):c.1960T>G (p.Ter654Gly)
NC_000004.12:g.1004391T>G
CM000666.2:g.1004391T>G
NC_000004.11:g.998179T>G
CM000666.1:g.998179T>G
NC_000004.10:g.988179T>G
NG_008103.1:g.22395T>G
ENST00000247933.9:c.1960T>G
ENST00000514224.2:c.1960T>G
ENST00000652070.1:n.2016T>G
ENST00000247933.8:c.1960T>G
ENST00000514224.1:c.1564T>G
ENST00000514698.5:n.2071T>G
NM_000203.4:c.1960T>G
NR_110313.1:n.2052T>G
NM_000203.5:c.1960T>G
NM_001363576.1:c.1564T>G

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM5_Supporting PM3 PM4

• Not Met criteria codes: PS3 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.1960T>G in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Gly), resulting in an increase in the length of the protein (PM1). One patient with "Hurler-Scheie" syndrome, who is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909), has been reported. The variants were confirmed to be in trans (PMID: 7550232) (PM3; insufficient evidence to apply PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 8.475e-7 (1/1179958 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). When the variant was expressed in COS cells, the intracellular activity of IDUA was low (negative control 1.3 (U/mg cell protein, wild type 14.5 (U/mg cell protein, variant 2.5 (U/mg cell protein), approximately 10% wild type ( PMID: 7550232). This is higher than the LD VCEP's threshold for IDUA activity for PS3_Supporting (<2%), therefore, PS3 was not applied. Other IDUA stop loss variants have been reported in patients with MPS1. 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 (PM5_Supporting). The other variants are c.1961A>T (p.Ter654Cys) ((Bach et al, 1993, PMID: 8328452) and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762). 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 Version 1.0.0): PM4, PM3, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is 8.475e-7 (1/1179958 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).
• PM5_Supporting: Other IDUA stop loss variants have been reported in patients with MPS1. 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 (PM5_Supporting). The other variants are c.1961A>T (p.Ter654Cys) (Bach et al, 1993, PMID: 8328452) and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762).
• PM3: One patient with "Hurler-Scheie" syndrome, who is compund heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, p.Gln70Ter, has been reported. The variants were confirmed to be in trans (PMID: 7550232) (PM3).
• PM4: The NM_000203.5:c.1960T>G in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Gly), resulting in an increase in the length of the protein (PM1).

Not Met criteria codes

• PS3: When the variant was expressed in COS cells, the intracellular activity of IDUA was low (negative control 1.3 (U/mg cell protein, wild type 14.5 (U/mg cell protein, variant 2.5 (U/mg cell protein), approximately 10% wild type ( PMID: 7550232). This is higher than the LD VCEP's threshold for IDUA activity for PS3_Supporting (<2%), therefore, PS3 was not applied.
• PP4: One patient, described as having "Hurler-Scheie" syndrome, has been reported with the variant. However, insufficient data is available to apply PP4.