4-1004393-A-T

Variant names:

• chr4-1004393-A-T
• rs199794428
• NM_000203.5:c.1962A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5_Supporting PS3_Supporting PM2 PM4 PM3_Supporting

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA353725/MONDO:0001586/091

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 stop_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 0.370
• Publications: 2 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: ClinGen, Myriad Women’s Health
• Scheie syndrome

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

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• PM5: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1962A>T	p.Ter654Cysext*?	stop_lost	Exon 14 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.1566A>T	p.Ter522Cysext*?	stop_lost	Exon 13 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.2054A>T		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1962A>T	p.Ter654Cysext*?	stop_lost	Exon 14 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1962A>T	p.Ter654Cysext*?	stop_lost	Exon 14 of 14	ENSP00000247933.4
	IDUA	ENST00000514698.5	TSL:5	n.2073A>T		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1

Dec 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.7
DANN	Benign	0.56
Eigen	Benign	0.097
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.12	N
PhyloP100		0.37
Vest4		0.15
GERP RS		0.072
Mutation Taster		=4/196	disease causing

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: rs199794428; hg19: chr4-998181;