rs777295041

Variant names:

• chr4-1000880-A-G
• rs777295041
• NM_000203.5:c.386-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2_Supporting PM3 PP4 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.386-2A>G variant in IDUA, reported in older literature as 474-2A>G, occurs within the canonical splice acceptor site of intron 3. RT-PCR studies revealed that this variant results in skipping of exon 4 (PMID:8019563). This is expected to result in an in-frame deletion of 36 amino acids which represents <10% of the protein. The in silico predictor SpliceAI does not predict the use of a cryptic splice site nearby (PVS1_Moderate). The variant has been identified in more than 20 individuals who have been diagnosed with MPS1, including 3 individuals with documented laboratory values showing deficiency of IDUA activity, two of who also have elevated urine GAGs (PMIDs: 23430808, 23837464) (PP4). Of these individuals at least 17 are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP including c.1205G>A, p.Trp402Ter (at least 10 individuals) (PMIDs: 8019563, 28752568), c.1855C>T (p.Arg619Ter) (PMID:11735025), p.Pro533Arg (PMID:8019563), c.208C>T (p.Gln70Ter) (at least 2 individuals) (PMIDs: 23430808, 28752568), and c.540_544delGAATG (p.Trp180Ter) (PMID:28752568), and at least two are homozygous for the variant homozygotes (PMID:28752568, 31194252) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and either c.236C>T (p.Ala79Val) (PMID:28752568), c.653T>C (p.Leu218Pro) (PMID:28752568), c.41T>G (p.Leu14Arg) (PMID:28752568), p.Arg383His (PMID:23837464) or p.Leu238Gln (PMID:24368159); The allelic data from these patients will be used in the classifications of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0.is 0.0002086 (249/1179062 alleles; no homozygotes) 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).There is a ClinVar entry for this variant (Variation ID: 222994). In summary, this variant meets the criteria to be classified as pathogenic for MPS1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PVS1_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA356991/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: IDUA NM_000203.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 3.96
• Publications: 5 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Hurler syndrome

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

• PVS1: 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.

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.386-2A>G		splice_acceptor intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.-11-2A>G		splice_acceptor intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.474-2A>G		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.386-2A>G		splice_acceptor intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.386-2A>G		splice_acceptor intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.461-2A>G		splice_acceptor intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000360 AC: 9 AN: 250194 AF XY: 0.0000295

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: 0.0000798

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 249 AN: 1459978 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 120 AN XY: 726420

African (AFR) AF: 0.0000598 AC: 2 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000220 AC: 244 AN: 1111044

Other (OTH) AF: 0.0000497 AC: 3 AN: 60334

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000575 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Mucopolysaccharidosis type 1 (5)
4	-	-	not provided (4)
1	-	-	Hurler syndrome (1)
1	-	-	Mucopolysaccharidosis, MPS-I-H/S (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Benign	0.85
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		4.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.61		Position offset: 2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs777295041; hg19: chr4-994668;