4-1002459-C-G

Variant names:

• chr4-1002459-C-G
• rs794727896
• NM_000203.5:c.1163C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2_Supporting PP4 PM3_Strong PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1163C>G variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 388 (p.Thr388Arg). Two patients with this variant had IDUA deficiency within the affected range in leukocytes (specific values not provided) and clinical features specific to MPS I including corneal clouding (PMID:17606547, 30120129). This variant has been detected in at least 10 individuals with MPS I who were heterozygous for the variant and a pathogenic or likely pathogenic variant classified by the ClinGen Lysosomal Diseases VCEP (variants: c.1139A>G, c.1205G>A, c.1855C>T, c.1861C>T); however, phase was not confirmed in any case (PMID:14516901, 17606547, 21253827, 21963080, 28752568, 30120129) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006003 (69/1149360 alleles) in the NFE population (gnomAD v2.1.1 is 0.00001342 with 1/74540 alleles in the NFE population), which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.824 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). 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): PM3_Strong, PM2_Supporting, PP3_Moderate, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA91169370/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 5.91
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1163C>G	p.Thr388Arg	missense	Exon 8 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.767C>G	p.Thr256Arg	missense	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1251C>G		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1163C>G	p.Thr388Arg	missense	Exon 8 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1163C>G	p.Thr388Arg	missense	Exon 8 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1238C>G	p.Thr413Arg	missense	Exon 9 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 153708 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000471 AC: 66 AN: 1401078 Hom.: 0 Cov.: 35 AF XY: 0.0000419 AC XY: 29 AN XY: 691618

African (AFR) AF: 0.00 AC: 0 AN: 31566

American (AMR) AF: 0.00 AC: 0 AN: 36040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.00 AC: 0 AN: 35828

South Asian (SAS) AF: 0.00 AC: 0 AN: 79736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.0000610 AC: 66 AN: 1081336

Other (OTH) AF: 0.00 AC: 0 AN: 58072

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Mucopolysaccharidosis type 1 (5)
2	-	-	not provided (2)
1	-	-	Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.99
MPC		0.81
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.83
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs794727896; hg19: chr4-996247;