chr4-1002387-C-G

Variant names:

• chr4-1002387-C-G
• rs121965032
• NM_000203.5:c.1091C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2_Supporting PM5 PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1091C>G variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 364 (p.Thr364Arg). To our knowledge, this variant has not been reported in the literature in any individuals with MPS I. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.901 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). Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as a VUS 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): PM2_Supporting, PP3_Moderate, PM5.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA355963316/MONDO:0001586/091

• Frequency: Genomes: not found (cov: 34)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 4.79

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1091C>G	p.Thr364Arg	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.1091C>G	p.Thr364Arg	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1091C>G	p.Thr364Arg	missense_variant	Exon 8 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1198C>G		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1	n.1147C>G		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000204 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1 Uncertain:1

Dec 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.1091C>G variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 364 (p.Thr364Arg). To our knowledge, this variant has not been reported in the literature in any individuals with MPS I. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. The computational predictor REVEL gives a score of 0.901 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). Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as a VUS 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): PM2_Supporting, PP3_Moderate, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

Aug 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr364 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9391892, 16435211, 29801497). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with IDUA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 364 of the IDUA protein (p.Thr364Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.80
MVP		0.99
MPC		0.79
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121965032; hg19: chr4-996175;