rs780615798

Variant names:

• chr4-1000698-G-C
• rs780615798
• NM_000203.5:c.385+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PP4_Moderate PM3 PM2_Supporting PS1_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.385+1G>C variant in IDUA occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3 out of 14 exons, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients from a Mexican cohort have been reported with "low or no activity of α-L-iduronidase" and treated with enzyme replacement therapy. One patient from Spain was reported with clinical features consistent with MPS1, elevated urine GAGs, and deficient IDUA activity, meeting three criteria for PP4 (PP4_Moderate). Both of the individuals from Mexico are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP - c.46_57del ((p.Ser16_Ala19del) (ClinVar variation ID: 92643) in one patient and c.1598C>G (p.Pro533Arg) (ClinVar variation ID: 11910) in the other patient. Phase was not confirmed in either patient (PMID:25098213) (2 x 0.5 points = 1 point) (PM3). The patient from Spain is compound heterozygous for the variant and c.655G>C (p.Gy219Arg). The allelic data from this patient will be used in the classification of p.Gly219 Arg and is not included here to avoid circular logic. The variant is absent in gnomAD v4.1.0. (PM2_Supporting). Another variant at the same position, c.385+1G>A (ClinGen Allele Registry ID: CA355961228), has been classified as pathogenic by the ClinGen LD VCEP (PS1_Supporting, PMID:37352859). In summary, this variant meets the criteria to be classified as pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 1.0.0: PVS1, PM3, PS1_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2801887/MONDO:0001586/091

• Frequency: Genomes: not found (cov: 34)
• Consequence: IDUA NM_000203.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 6.75
• 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS1: 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.385+1G>C		splice_donor_variant, intron_variant	Intron 3 of 13	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.-12+1G>C		splice_donor_variant, intron_variant	Intron 2 of 12		NP_001350505.1
IDUA	NR_110313.1	n.473+1G>C		splice_donor_variant, intron_variant	Intron 3 of 13
IDUA	XM_047415650.1	c.385+1G>C		splice_donor_variant, intron_variant	Intron 3 of 11		XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.385+1G>C		splice_donor_variant, intron_variant	Intron 3 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249514 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Jul 17, 2018

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.385+1G>C variant in IDUA occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3 out of 14 exons, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients from a Mexican cohort have been reported with "low or no activity of α-L-iduronidase" and treated with enzyme replacement therapy. One patient from Spain was reported with clinical features consistent with MPS1, elevated urine GAGs, and deficient IDUA activity, meeting three criteria for PP4 (PP4_Moderate). Both of the individuals from Mexico are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP - c.46_57del ((p.Ser16_Ala19del) (ClinVar variation ID: 92643) in one patient and c.1598C>G (p.Pro533Arg) (ClinVar variation ID: 11910) in the other patient. Phase was not confirmed in either patient (PMID: 25098213) (2 x 0.5 points = 1 point) (PM3). The patient from Spain is compound heterozygous for the variant and c.655G>C (p.Gy219Arg). The allelic data from this patient will be used in the classification of p.Gly219 Arg and is not included here to avoid circular logic. The variant is absent in gnomAD v4.1.0. (PM2_Supporting). Another variant at the same position, c.385+1G>A (ClinGen Allele Registry ID: CA355961228), has been classified as pathogenic by the ClinGen LD VCEP (PS1_Supporting, PMID: 37352859). In summary, this variant meets the criteria to be classified as pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 1.0.0: PVS1, PM3, PS1_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)

Mar 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 of the IDUA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is present in population databases (rs780615798, gnomAD no frequency). Disruption of this splice site has been observed in individuals with Hurler or Hurler/Scheie syndrome (PMID: 25098213). ClinVar contains an entry for this variant (Variation ID: 551966). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Jun 21, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hurler syndrome Pathogenic:1

May 12, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
LIST_S2	Benign	0.0	.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		6.8
PROVEAN	Benign	0.0	.;.;.;.
Sift	Pathogenic	0.0	.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.
Vest4		0.0
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs780615798; hg19: chr4-994486;