rs754949360

Variant names:

• chr4-1002444-G-A
• rs754949360
• NM_000203.5:c.1148G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_Supporting PP1_Moderate PP4_Moderate PM2_Supporting PM3 PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1148G>A variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 383 (p.Arg383His). At least five patients with this variant had documented IDUA deficiency within the affected range in leukocytes, enzyme replacement therapy resulting in a significant reduction in total urine GAGs, and/or clinical features specific to MPS I including corneal and joint involvement (PMID:23786846, 23837464, 31090850) (PP4_Moderate). This variant has been detected in at least 1 individual with MPS I who was homozygous for the variant (PMID:7550242, 0.5 points). It has also been detected in at least 8 individuals who were compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; variants: c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909)(PMID:23837464, 0.5 points); c.266G>A (p.Arg89Gln) ( (PMID:31194252, 0.5 points), c.386-2A>G (ClinVar Variation ID: 222994) (PMID:23837464, 2 unrelated patients, 2 x 0.5 points), c.266G>A (p.Arg89Gln) (ClinVar Variation ID: 11922) (PMID:31194252, 0.5 points), c.979G>C (p.Ala327Pro) (Variation ID: 167190) (PMID:12559846, 23837464, 0.5 points), c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID:12559846, 23837464, 0.5 points), c.1598C>G (p.Pro533Arg) (ClinVar Variation ID: 11910) (PMID:30419879, 0.5 points); however, phase was not confirmed in any case (Total >4 points) (PM3_Very Strong). One pair of sibling with MPS I and compound heterozygous for the variant and p.Gln70Ter, and another pairs of siblings compound heterozygous for the variant and c.386-2A>G (aka c.474-2A>G) ( PMID:23837464) (PP1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001653 (14/84692 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When expressed in CHO cells, the activity of the variant was <2% wild type activity (PS3_Supporting). The computational predictor REVEL gives a score of 0.874 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID:36413997) (PP3_Moderate). There is a ClinVar entry for the variant (Variation ID: 558189). 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): PM3_Very Strong, PP1_Moderate, PP3_Moderate, PP4_Moderate, PS3_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/CA2802205/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.83

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 Pathogenic. Variant got 10 ACMG points.

• PS3: 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1148G>A	p.Arg383His	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1148G>A	p.Arg383His	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1148G>A	p.Arg383His	missense_variant	Exon 8 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1255G>A		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1	n.1204G>A		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000328 AC: 5 AN: 152662 Hom.: 0 AF XY: 0.0000364 AC XY: 3 AN XY: 82372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000865

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000336

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 23 AN: 1402554 Hom.: 0 Cov.: 35 AF XY: 0.0000231 AC XY: 16 AN XY: 692730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000831

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000627 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000193 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Sep 15, 2020

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.1148G>A variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 383 (p.Arg383His). At least five patients with this variant had documented IDUA deficiency within the affected range in leukocytes, enzyme replacement therapy resulting in a significant reduction in total urine GAGs, and/or clinical features specific to MPS I including corneal and joint involvement (PMID: 23786846, 23837464, 31090850) (PP4_Moderate). This variant has been detected in at least 1 individual with MPS I who was homozygous for the variant (PMID: 7550242, 0.5 points). It has also been detected in at least 8 individuals who were compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; variants: c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909)(PMID: 23837464, 0.5 points); c.266G>A (p.Arg89Gln) ( (PMID: 31194252, 0.5 points), c.386-2A>G (ClinVar Variation ID: 222994) (PMID: 23837464, 2 unrelated patients, 2 x 0.5 points), c.266G>A (p.Arg89Gln) (ClinVar Variation ID: 11922) (PMID: 31194252, 0.5 points), c.979G>C (p.Ala327Pro) (Variation ID: 167190) (PMID: 12559846, 23837464, 0.5 points), c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 12559846, 23837464, 0.5 points), c.1598C>G (p.Pro533Arg) (ClinVar Variation ID: 11910) (PMID: 30419879, 0.5 points); however, phase was not confirmed in any case (Total >4 points) (PM3_Very Strong). One pair of sibling with MPS I and compound heterozygous for the variant and p.Gln70Ter, and another pairs of siblings compound heterozygous for the variant and c.386-2A>G (aka c.474-2A>G) ( PMID: 23837464) (PP1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001653 (14/84692 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When expressed in CHO cells, the activity of the variant was <2% wild type activity (PS3_Supporting). The computational predictor REVEL gives a score of 0.874 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for the variant (Variation ID: 558189). 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): PM3_Very Strong, PP1_Moderate, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

Mar 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 383 of the IDUA protein (p.Arg383His). 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 missense change has been observed in individual(s) with IDUA-related conditions (PMID: 7550242, 12559846, 23786846). ClinVar contains an entry for this variant (Variation ID: 558189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IDUA function (PMID: 12559846). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

May 31, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hurler syndrome Pathogenic:1

May 03, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.72
MVP		0.98
MPC		0.84
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.78
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs754949360; hg19: chr4-996232;