4-1001510-C-G

Variant names:

• chr4-1001510-C-G
• rs776098539
• NM_000203.5:c.536C>G

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_Moderate PM3 PM2_Supporting PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.4:c.536C>G variant in IDUA is a missense variant predicted to cause substitution of Threonine by Arginine at amino acid 179 (p.Thr179Arg). This variant has been reported in at least eight individuals with MPS I (PMID:35433540, 21480867, 29095814, 34813777). This variant has been reported in at least eight individuals with MPS I (PMID:35433540, 21480867, 29095814, 34813777): one is homozygous for this variant (PMID:21480867, 0.5 points), six are compound heterozygous for this variant and a second variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP including c.877G>A p.(Trp626Ter) (PMID:35433540, phase confirmed, 1 point), c.236C>T p.(Ala79Val) (PMID:21480867, 2 patients, phase unconfirmed, 2 x 0.5 points), c.1898C>T p.(Ser633Leu) (PMID:21480867, 2 patients, phase unconfirmed, 2 x 0.5 points), c.1601C>A p.(Ser534Ter) (PMID:34813777, phase not confirmed, 0.5 point). One additional patient had a clinical diagnosis and carried this variant but a second variant was not detected. 4 points (PM3_VeryStrong). One patient with this variant present in the homozygous state has been reported with a clinical diagnosis of Hurler syndrome, presenting with delayed development, macrocephaly, congenital dermal melanocytosis, and hepatosplenomegaly; this patient also had reduced IDUA enzyme activity (0.1 nmol/h/mg, reference range 27.2-52) and increased excretion of urinary dermatan sulfate and heparan sulfate (PMID:21480867) (PP4_moderate). The population minor allele frequency in gnomAD v4.1.0 is 8.5e-7 (1/1,179,952 alleles), 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 0.927 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). Other missense variants at the same position have been reported in individuals with MPS1, including c.536C>T p.(Thr179Met) (PMID:32670797, ClinVar ID: 1455223), and p.Thr179Lys (PMID:28752568, ClinVar ID: 1455223). The classification of c.536C>G (p.Thr179Arg) will be used in the assessment of the other variants at Thr179 and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 556358). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_very strong; PP3_moderate; PP4_moderate; 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/CA355961718/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.60

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 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.
• 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.536C>G	p.Thr179Arg	missense_variant	Exon 5 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.536C>G	p.Thr179Arg	missense_variant	Exon 5 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460944 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726766

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 179 of the IDUA protein (p.Thr179Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21480867). ClinVar contains an entry for this variant (Variation ID: 556358). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. This variant disrupts the p.Thr179 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been observed in individuals with IDUA-related conditions (PMID: 28752568), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Dec 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.4:c.536C>G variant in IDUA is a missense variant predicted to cause substitution of Threonine by Arginine at amino acid 179 (p.Thr179Arg). This variant has been reported in at least eight individuals with MPS I (PMID: 35433540, 21480867, 29095814, 34813777). This variant has been reported in at least eight individuals with MPS I (PMID: 35433540, 21480867, 29095814, 34813777): one is homozygous for this variant (PMID: 21480867, 0.5 points), six are compound heterozygous for this variant and a second variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP including c.877G>A p.(Trp626Ter) (PMID: 35433540, phase confirmed, 1 point), c.236C>T p.(Ala79Val) (PMID: 21480867, 2 patients, phase unconfirmed, 2 x 0.5 points), c.1898C>T p.(Ser633Leu) (PMID: 21480867, 2 patients, phase unconfirmed, 2 x 0.5 points), c.1601C>A p.(Ser534Ter) (PMID: 34813777, phase not confirmed, 0.5 point). One additional patient had a clinical diagnosis and carried this variant but a second variant was not detected. 4 points (PM3_VeryStrong). One patient with this variant present in the homozygous state has been reported with a clinical diagnosis of Hurler syndrome, presenting with delayed development, macrocephaly, congenital dermal melanocytosis, and hepatosplenomegaly; this patient also had reduced IDUA enzyme activity (0.1 nmol/h/mg, reference range 27.2-52) and increased excretion of urinary dermatan sulfate and heparan sulfate (PMID: 21480867) (PP4_moderate). The population minor allele frequency in gnomAD v4.1.0 is 8.5e-7 (1/1,179,952 alleles), 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 0.927 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). Other missense variants at the same position have been reported in individuals with MPS1, including c.536C>T p.(Thr179Met) (PMID: 32670797, ClinVar ID: 1455223), and p.Thr179Lys (PMID: 28752568, ClinVar ID: 1455223). The classification of c.536C>G (p.Thr179Arg) will be used in the assessment of the other variants at Thr179 and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 556358). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_very strong; PP3_moderate; PP4_moderate; PM2_supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

Apr 25, 2023

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.536C>G (p.Thr179Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250946 control chromosomes (gnomAD). c.536C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucopolysaccharidosis Type 1 (e.g. Wang_2012, Hu_2018, Fang_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34813777, 29095814, 21480867). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 10, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hurler syndrome Pathogenic:1

Jan 26, 2018

Counsyl

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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;.;.;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.90
MutPred		0.62		.;Gain of MoRF binding (P = 0.0654);.;.;.;
MVP		1.0
MPC		0.81
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.90
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs776098539; hg19: chr4-995298;