rs794727701

Variant names:

• chr4-1001467-G-A
• rs794727701
• NM_000203.5:c.494-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1001467-G-A
• chr4-1001467-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PM3 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.494-1G>A variant in IDUA is a canonical splice acceptor variant. This variant is predicted to cause either an in-frame deletion of exon 5 including Glu182 (PVS1), or an activation of a cryptic splice site, leading to a frameshift and premature truncation (p.Arg166ThrfsTer27) (PVS1). The available experimental data do not definitively confirm either of these outcomes, and hence the decision has been made by the ClinGen IDUA VCEP to downgrade the strength of this criterion to PVS1_Strong.The highest population minor allele frequency in gnomAD v4.1.0. is 8.477e-7 (1/1179702 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).This variant has been reported primarily in Turkish patients, with at least five instances in the literature: four times in a homozygous genotype (PM3), and once as part of a compound heterozygous genotype with a variant (c.826G>A) that could be considered likely pathogenic (PMID:21394825). Segregation studies for these patients were not available in this paper. There is a report of the variant in ClinVar (Variation ID: 557942). In summary, this variant meets the criteria to be classified as likely 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, PM2_Supporting, PM3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA355961634/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.73

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.494-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 13	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.494-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250814 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135798

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460524 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726606

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Oct 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IDUA c.494-1G>A 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of IDUA function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 5' donor site. The variant allele was found at a frequency of 4e-06 in 250814 control chromosomes. c.494-1G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1/Hurler syndrome (example: Atceken_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27511503). ClinVar contains an entry for this variant (Variation ID: 557942). Based on the evidence outlined above, the variant was classified as pathogenic. -

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.494-1G>A variant in IDUA is a canonical splice acceptor variant. This variant is predicted to cause either an in-frame deletion of exon 5 including Glu182 (PVS1), or an activation of a cryptic splice site, leading to a frameshift and premature truncation (p.Arg166ThrfsTer27) (PVS1). The available experimental data do not definitively confirm either of these outcomes, and hence the decision has been made by the ClinGen IDUA VCEP to downgrade the strength of this criterion to PVS1_Strong. The highest population minor allele frequency in gnomAD v4.1.0. is 8.477e-7 (1/1179702 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). This variant has been reported primarily in Turkish patients, with at least five instances in the literature: four times in a homozygous genotype (PM3), and once as part of a compound heterozygous genotype with a variant (c.826G>A) that could be considered likely pathogenic (PMID: 21394825). Segregation studies for these patients were not available in this paper. There is a report of the variant in ClinVar (Variation ID: 557942). In summary, this variant meets the criteria to be classified as likely 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, PM2_Supporting, PM3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

Hurler syndrome Pathogenic:1

Apr 20, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.69		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs794727701; hg19: chr4-995255;