chr4-1004391-T-C

Variant names:

• chr4-1004391-T-C
• rs387906504
• NM_000203.5:c.1960T>C

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM4 PM3 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA355966127/MONDO:0001586/091

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 stop_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 0.123
• Publications: 8 publications found

Genes affected

IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]

IDUA Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1960T>C	p.Ter654Argext*?	stop_lost	Exon 14 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1564T>C	p.Ter522Argext*?	stop_lost	Exon 13 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.2052T>C		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1960T>C	p.Ter654Argext*?	stop_lost	Exon 14 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1960T>C	p.Ter654Argext*?	stop_lost	Exon 14 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.2035T>C	p.Ter679Argext*?	stop_lost	Exon 15 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis type 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.4
DANN	Benign	0.58
Eigen	Benign	0.055
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.012	N
PhyloP100		0.12
Vest4		0.15
GERP RS		-0.75
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906504; hg19: chr4-998179;