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 label mismatch: IDUA vs undefined
  • 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.1960T>C (p.Ter654Arg)

CA355966127

960079 (ClinVar)

Gene: IDUA
Condition: mucopolysaccharidosis type 1
Inheritance Mode: Autosomal recessive inheritance
UUID: 42eac213-5f99-4af7-aef5-4fb153dac576
Approved on: 2025-04-07
Published on: 2025-04-07

HGVS expressions

NM_000203.5:c.1960T>C
NM_000203.5(IDUA):c.1960T>C (p.Ter654Arg)
NC_000004.12:g.1004391T>C
CM000666.2:g.1004391T>C
NC_000004.11:g.998179T>C
CM000666.1:g.998179T>C
NC_000004.10:g.988179T>C
NG_008103.1:g.22395T>C
ENST00000247933.9:c.1960T>C
ENST00000514224.2:c.1960T>C
ENST00000652070.1:n.2016T>C
ENST00000247933.8:c.1960T>C
ENST00000514224.1:c.1564T>C
ENST00000514698.5:n.2071T>C
NM_000203.4:c.1960T>C
NR_110313.1:n.2052T>C
NM_001363576.1:c.1564T>C
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Pathogenic

Met criteria codes 4
PM2_Supporting PM4 PM3_Very Strong PP4
Not Met criteria codes 2
PM5 PS3

Evidence Links 1

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.1960T>C in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Arg). Sequence analysis of cDNA (by 3'RACE) showed that the variant results in an increase in the length of the protein by 38 amino acids (PMID: 29282708) (PM4). Seven patients have been reported with the variant, including patients with clinical features consistent with MPS 1, and deficient IDUA activity (PMID: 21394825, 29282708) (PP4). Of these patients, five are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, including c.935G>A (p.Trp312Ter), phase unconfirmed (0.5 points) (PMID: 29282708), c.1138C>T (p.Gln380Ter), confirmed in trans (1 point) (PMID: 29282708), 46_57del12, phase not confirmed (0.5 points) (PMID: 21394825), c.208C>T (p.Gln70Ter), phase not confirmed (0.5 points) (PMID: 21394825), and c.266G>A (p.Arg89Gln) (PMID: 29282708), phase not confirmed (0.5 points). Two patients have been reported to be homozygous for the variant (2 x 0.5 points) (PMID: 29282708). Total 4 points (PM3_VeryStrong). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). When expressed in COS-7 cells, the variant resulted in 6% wild type activity, and Western blot pattern was abnormal (PMID: 29282708). The activity the LD VCEP's threshold for PS3_Supporting (<2%) and therefore, PS3_Supporting was not applied. Other IDUA stop loss variants have been reported in patients with MPS 1 including c.1960T>G (p.Ter654Gly) (Tieu et al, 1995, PMID: 7550232), and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762) and c.1962A>T (p.Ter654Cys) (Bach et al, 1993, PMID: 8328452). The classification of c.1960T>C (p.Ter654Arg) will be used in the assessment of those other variants. Therefore, PM5 was not applied here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 960079) 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 Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_VeryStrong, PM1, PM4, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025)
Met criteria codes
PM2_Supporting
The variant is absent in gnomAD v4.1.0. (PM2_Supporting).
PM4
The NM_000203.5:c.1960T>C in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Arg). Sequence analysis of cDNA (by 3'RACE) showed that the variant results in an increase in the length of the protein by 38 amino acids (PMID: 29282708) (PM1).
PM3_Very Strong
Seven patients (5 from Thailand and 2 from Poland) have been reported with the variant. Of these patients, five are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, including c.935G>A (p.Trp312Ter), phase unconfirmed (0.5 points) (PMID: 29282708), c.1138C>T (p.Gln380Ter), confirmed in trans (1 point) (PMID: 29282708), 46_57del12, phase not confirmed (0.5 points) (PMID: 21394825), c.208C>T (p.Gln70Ter), phase not confirmed (0.5 points) (PMID: 21394825), and c.266G>A (p.Arg89Gln) (PMID: 29282708), phase not confirmed (0.5 points). Two patients have been reported to be homozygous for the variant (2 x 0.5 points) (PMID: 29282708). Total 4 points (PM3_VeryStrong).
PP4
Seven patients (5 from Thailand and 2 from Poland) have been reported with the variant, including patients with clinical features consistent with MPS 1 and deficient IDUA activity (PMID: 21394825, 29282708) (PP4).
Not Met criteria codes
PM5
Other IDUA stop loss variants have been reported in patients with MPS 1 including c.1960T>G (p.Ter654Gly) (Tieu et al, 1995, PMID: 7550232), and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762) and c.1962A>T (p.Ter654Cys) (Bach et al, 1993, PMID: 8328452). The classification of c.1960T>C (p.Ter654Arg) will be used in the assessment of those other variants. Therefore, PM5 was not applied here to avoid circular logic.
PS3
When expressed in COS-7 cells, the variant resulted in 6% wild type activity, and Western blot pattern was abnormal (PMID: 29282708). This exceeds the LD VCEP's threshold for PS3_Supporting (<2%) and therefore, PS3_Supporting was not applied.

Curation History
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