4-1001672-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_SupportingPM3_StrongPVS1_StrongPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5: c.590-7G>A variant in IDUA occurs within the splice acceptor site motif of intron 5. RT-PCR analysis revealed skipping of biologically-relevant-exon 6/14, or, rarely, intron 5 inclusion, resulting mainly in splicing at nt -28 of intron 5, and also a very small amount of normal IDUA mRNA (PMID:8213840; 9748610) (PVS1_Strong (RNA)). This variant is also reported as IDUA:c. 678-7 G>A in older literature (PMID:8213840). This variant has been detected in at least 10 individuals with MPS I, all compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, all phase unconfirmed, including c.208C>T (p.Gln70Ter) (PMID:28752568, ClinVar Variation ID: 11909, 0.5 points), c.1205G>A (p.Trp402Ter) (PMID:28752568, CinVar Variation ID: 11908, 7 patients, max 2 x 0.5 points), and (c.1029C>G (p.Tyr343Ter) (C;inVar Variation ID: 550474, clinical lab, 0.5 points) (PM3_Strong). Total 2 points (PM3_Strong). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes, a significant reduction in urine GAGs upon treatment with enzyme replacement therapy, and clinical features specific to MPS I including arthropathy, corneal involvement, and valvular thickening. (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004241 (50/1178952 alleles) 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: 222996). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_strong, PM3_strong, PP4_moderate, 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/CA356990/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

IDUA
NM_000203.5 splice_region, intron

Scores

Splicing: ADA: 0.6696

Clinical Significance

Pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: -4.52

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 was made for transcript

Our verdict: Pathogenic. The variant received 11 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 rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.590-7G>A		splice_region_variant, intron_variant	Intron 5 of 13	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.590-7G>A		splice_region_variant, intron_variant	Intron 5 of 13	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000427

AC:

AN:

234380

AF XY:

0.00000779

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000936

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000338

AC:

AN:

1449800

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

721532

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33412

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44450

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26074

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39580

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86048

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

43342

Gnomad4 NFE exome

AF:

0.0000441

AC:

AN:

1110938

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60194

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000147029

AN:

0.0000147029

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:4Other:1

Dec 06, 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.590-7G>A variant in IDUA occurs within the splice acceptor site motif of intron 5. RT-PCR analysis revealed skipping of biologically-relevant-exon 6/14, or, rarely, intron 5 inclusion, resulting mainly in splicing at nt -28 of intron 5, and also a very small amount of normal IDUA mRNA (PMID: 8213840; 9748610) (PVS1_Strong (RNA)). This variant is also reported as IDUA:c. 678-7 G>A in older literature (PMID: 8213840). This variant has been detected in at least 10 individuals with MPS I, all compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, all phase unconfirmed, including c.208C>T (p.Gln70Ter) (PMID: 28752568, ClinVar Variation ID: 11909, 0.5 points), c.1205G>A (p.Trp402Ter) (PMID: 28752568, CinVar Variation ID: 11908, 7 patients, max 2 x 0.5 points), and (c.1029C>G (p.Tyr343Ter) (C;inVar Variation ID: 550474, clinical lab, 0.5 points) (PM3_Strong). Total 2 points (PM3_Strong). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes, a significant reduction in urine GAGs upon treatment with enzyme replacement therapy, and clinical features specific to MPS I including arthropathy, corneal involvement, and valvular thickening. (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004241 (50/1178952 alleles) 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: 222996). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_strong, PM3_strong, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

Jan 14, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The c.590-7G>A variant in IDUA has been reported in at least 10 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 8213840, 9748610) and has been identified in 0.001% (1/106874) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762411583). 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: 222996) as pathogenic by Counsyl, OMIM, and GeneReviews. Functional studies demonstrating that the variant activates a cryptic splice site provide some evidence that the c.590-7G>A variant may slightly impact protein function (PMID: 8213840). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the 3' splice region. Computational tools suggest a possible impact to splicing. However, this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is high' ly specific for MPS based on their Alpha-L-iduronidase protein levels being <1% consistent with disease (PMID: 9748610, 8213840). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with reported pathogenic variants, the phenotype of patients with the variant being highly specific for MPS, and evidence of aberrant splicing. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4, PS3_supporting (Richards 2015). -

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 5 of the IDUA gene. It does not directly change the encoded amino acid sequence of the IDUA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with Scheie syndrome (PMID: 8213840, 28752568). This variant is also known as 678-7G>A. ClinVar contains an entry for this variant (Variation ID: 222996). Studies have shown that this variant results in activation of a cryptic splice acceptor, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 8318992). For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Variant causes attenuated MPS I; creates alternate splice site, but (as old splice site is not obliterated) some normal enzyme is produced. -

Mucopolysaccharidosis, MPS-I-S

Pathogenic:1

Nov 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jun 19, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hurler syndrome

Pathogenic:1

Aug 30, 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_noAF

Benign

-0.86

CADD

Benign

6.3

DANN

Benign

0.65

Mutation Taster

=20/80

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.67

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 2

DS_AL_spliceai

0.31

Position offset: 7

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