rs794726878

Variant names:

• chr4-987137-T-C
• rs794726878
• NM_000203.5:c.53T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_Moderate PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.53T>C variant in IDUA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 18 (p.Leu18Pro). This variant has been detected in at least 10 individuals with MPS I. This variant has been detected in at least 10 individuals with MPS I. Of those individuals, three were homozygous for the variant (PMID 25256405, max 2 x 0.5 = 1 point). Four of the remaining individuals are compound heterozygous for this variant and a second variant that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP including c.1205G>A p.(Trp402Ter) (ClinVar Variation ID: 11908) (PMID 31194252, at least one patient, phase not confirmed, 0.5 point), c.208C>T p.(Gln70Ter) (ClinVar Variation ID: 11909) (PMID 31194252, 255574391 2 patients, phase not confirmed, 2 x 0.5 point), and c.1487C>G p.(Pro496Arg) (PMID 31194252, 1 patient, phase not confirmed, 0.25 point). Two patients are compound heterozygous for the variant and c.1163C>A, p.(Thr388Lys), however the allelic data for these patients will be used to support the classification of Thr388Lys and is not included here in order to avoid circular logic (2.75 points, PM3_strong). One patient with this variant present in the homozygous state has been reported with a clinical diagnosis of attenuated MPS1, presenting with reduced IDUA enzyme activity (0.73 nmol/h/mg, reference range 32-56) and increased GAG excretion in urine (188ug GAGs/g creatinine, age-related reference 67-124). His brother, also homozygous for the variant is reported to have attenuated MPS1, with similar clinical features (PMID 25256405) (PP4_moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002779 (1/35,980 alleles) in the Admixed American 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 0.319 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. There is a ClinVar entry for this variant (Variation ID: 193062). 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, PP4_moderate, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 19, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA238566/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 36)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 0.633
• Publications: 5 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]

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

DGKQ (HGNC:2856): (diacylglycerol kinase theta) The protein encoded by this gene contains three cysteine-rich domains, a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. It is localized in the speckle domains of the nucleus, and mediates the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• 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.53T>C	p.Leu18Pro	missense	Exon 1 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_134425.4		c.576+3991A>G		intron	N/A	NP_602297.1	Q9H2B4-2
	IDUA	NR_110313.1		n.141T>C		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.53T>C	p.Leu18Pro	missense	Exon 1 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398520.6	TSL:1	c.576+3991A>G		intron	N/A	ENSP00000381532.2	Q9H2B4-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 52646 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: 0.00000236 AC: 3 AN: 1271464 Hom.: 0 Cov.: 36 AF XY: 0.00000480 AC XY: 3 AN XY: 625068

African (AFR) AF: 0.00 AC: 0 AN: 25150

American (AMR) AF: 0.00 AC: 0 AN: 20716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20510

East Asian (EAS) AF: 0.00 AC: 0 AN: 27400

South Asian (SAS) AF: 0.00 AC: 0 AN: 63772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3650

European-Non Finnish (NFE) AF: 0.00000292 AC: 3 AN: 1026342

Other (OTH) AF: 0.00 AC: 0 AN: 52364

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 74240

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hurler syndrome (3)
3	-	-	Mucopolysaccharidosis type 1 (3)
2	1	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.48
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.4	L
PhyloP100		0.63
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0	B
Vest4		0.38
MutPred		0.37		Gain of loop (P = 0.0045)
MVP		0.62
MPC		0.30
ClinPred		0.54	D
GERP RS		-1.4
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.74
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794726878; hg19: chr4-980925;