rs777295041

Positions:

chr4-1000880-A-G

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePP4PM2_SupportingPM3

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

Scores

Splicing: ADA: 0.9998

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.96

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.386-2A>G		splice_acceptor_variant		ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.386-2A>G		splice_acceptor_variant		2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250194

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135664

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

726420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000220

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000514

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000495

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change affects an acceptor splice site in intron 3 of the IDUA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs777295041, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis type I (PMID: 8019563, 11735025, 23837464, 24368159). This variant is also known as c.474-2 a>g and Int3-2a>g. ClinVar contains an entry for this variant (Variation ID: 222994). Studies have shown that disruption of this splice site results in exon skipping and introduces a premature termination codon (PMID: 8019563). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The c.386-2A>G variant in IDUA (also known as c.474-2A>G due to a difference in cDNA numbering) has been reported in at least 6 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 24368159, 11735025, 8019563) and has been identified in 0.008% (9/112774) of European (non-Finnish) chromosomes. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 222994) as pathogenic by Invitae, Counsyl, and GeneReviews. Functional studies demonstrating that the variant causes exon skipping provide some evidence that the c.386-2A>G variant may slightly impact protein function (PMID: 8019563). However, these types of assays may not accurately represent biological function. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in combination with 4 reported pathogenic variants in individuals with MPS increases the likelihood that the c.386-2A>G variant is pathogenic (PMID: 24368159, 11735025, 8019563). The phenotype of an individual heterozygous for this variant is highly specific for MPS based on undetectable iduronidase activity, consistent with disease (PMID: 28752568). In summary, this variant meets criteria to be classified as pathogenic for IDUA in an autosomal recessive manner based on the prediction that it causes loss of function of the IDUA gene, the presence of the variant in combination with other pathogenic variants in affected individuals, and functional studies. ACMG/AMP Criteria applied: PM3_strong, PM2, PVS1_moderate, PS3_supporting, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2018	Variant summary: IDUA c.386-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 245660 control chromosomes (gnomAD). The variant, c.386-2A>G, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Ghosh 2017, Beesley 2001), and most of the cases presented with a severe disease phenotype (Hurler syndrome). These data indicate that the variant is very likely to be associated with disease. Two publications reported no enzyme activity associated with this variant (Ghosh 2017, Bunge 1998). ClinVar has one entry for this variant after 2014 with a classification of "pathogenic". Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 9748610, 11735025, 21480867, 25525159, 8019563, 23837464, 28752568, 15300847, 24368159, 31194252, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2023	- -

Mucopolysaccharidosis, MPS-I-H/S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 08, 2022

- -

Hurler syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Benign

0.85

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

D;D;D

GERP RS

3.4

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over