NM_000203.5:c.99T>G

Variant names:

• chr4-987183-T-G
• rs10794537
• NM_000203.5:c.99T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.99T>G variant in IDUA is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 33 (p.His33Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.9605 (65474/68164 alleles; 31451 homozygotes; Grpmax Filtering AF 95% confidence = 0.9544) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92651). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145894/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.85 (55748 hom., cov: 38)
  • Exomes 𝑓: 0.81 (435164 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign reviewed by expert panel B:16
• Conservation: PhyloP100: -2.44
• Publications: 40 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]

SLC26A1 Gene-Disease associations (from GenCC):

• nephrolithiasis susceptibility caused by SLC26A1

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: 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.99T>G	p.His33Gln	missense_variant	Exon 1 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.99T>G	p.His33Gln	missense_variant	Exon 1 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129624 AN: 152032 Hom.: 55703 Cov.: 38

Gnomad AFR AF: 0.958

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.891

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.939

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.860

GnomAD2 exomes AF: 0.839 AC: 67457 AN: 80392 AF XY: 0.849

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.895

Gnomad EAS exome AF: 0.855

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.834

GnomAD4 exome AF: 0.810 AC: 1070032 AN: 1320386 Hom.: 435164 Cov.: 42 AF XY: 0.815 AC XY: 530301 AN XY: 650812

African (AFR) AF: 0.965 AC: 25675 AN: 26620

American (AMR) AF: 0.801 AC: 22320 AN: 27848

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 20741 AN: 23180

East Asian (EAS) AF: 0.857 AC: 24488 AN: 28560

South Asian (SAS) AF: 0.928 AC: 67400 AN: 72602

European-Finnish (FIN) AF: 0.790 AC: 25954 AN: 32854

Middle Eastern (MID) AF: 0.919 AC: 3579 AN: 3894

European-Non Finnish (NFE) AF: 0.794 AC: 834224 AN: 1050164

Other (OTH) AF: 0.835 AC: 45651 AN: 54664

GnomAD4 genome AF: 0.853 AC: 129714 AN: 152140 Hom.: 55748 Cov.: 38 AF XY: 0.854 AC XY: 63531 AN XY: 74384

African (AFR) AF: 0.958 AC: 39799 AN: 41544

American (AMR) AF: 0.819 AC: 12514 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.891 AC: 3092 AN: 3470

East Asian (EAS) AF: 0.853 AC: 4405 AN: 5166

South Asian (SAS) AF: 0.935 AC: 4516 AN: 4832

European-Finnish (FIN) AF: 0.789 AC: 8337 AN: 10568

Middle Eastern (MID) AF: 0.935 AC: 273 AN: 292

European-Non Finnish (NFE) AF: 0.800 AC: 54332 AN: 67954

Other (OTH) AF: 0.861 AC: 1821 AN: 2116

Alfa AF: 0.816 Hom.: 6355

Bravo AF: 0.858

TwinsUK AF: 0.786 AC: 2916

ALSPAC AF: 0.797 AC: 3073

ExAC AF: 0.853 AC: 10917

Asia WGS AF: 0.916 AC: 3163 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IDUA p.His33Gln variant was identified in the literature as polymorphism/benign in studies of patients with Mucopolysaccharidosis type I (MPS I) disease (Chkioua_2011_21639919, Azab_2017_28649516, Atceken_2016_27511503, Lin_2013_24053568, Li_2002_12509712). The variant was also identified in the following databases: dbSNP (ID: rs10794537) as “With Benign Allele”, ClinVar (3x, as benign), Clinvitae database (3x as benign). This variant was identified in the 1000 Genomes Project in 4467 of 5008 chromosomes (frequency: 0.9), the genome Aggregation Database (beta, October 19th 2016) in 9303 (4255 homozygous) of 10182 chromosomes (freq. 0.9), the Exome Aggregation Consortium database (August 8th 2016) in 92436 (39108 homozygous) of 110100 chromosomes (freq. 0.83) in the following populations: African in 9151 of 9570 chromosomes (freq. 0.95), other in 2692 of 3248 chromosomes (freq. 0.82), Latino in 13176 of 16524 chromosomes (freq. 0.8), European non Finnish in 35257 of 44264 chromosomes (freq. 0.8), Ashkenazi Jewish in 6104 of 6814 chromosomes (freq. 0.9), east Asian in 3947 of 4612 chromosomes (freq. 0.85), Finnish in 6417 of 8150 chromosomes (freq. 0.8), and South Asian in 15692 of 16918 chromosomes (freq. 0.8), increasing the likelihood this is a high frequency benign variant, seen in all populations. The p.His33 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 25, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1 Benign:4

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.99T>G variant in IDUA is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 33 (p.His33Gln). The highest population minor allele frequency in gnomAD v4.1.0 is 0.9605 (65474/68164 alleles; 31451 homozygotes; Grpmax Filtering AF 95% confidence = 0.9544) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92651). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mucopolysaccharidosis, MPS-I-H/S Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-I-S Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hurler syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.34
DANN	Benign	0.67
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.041	T;T
MetaRNN	Benign	7.3e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N;.
PhyloP100		-2.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.75	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.46	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0	B;.
Vest4		0.011
MutPred		0.40		Gain of MoRF binding (P = 0.1031);Gain of MoRF binding (P = 0.1031);
MPC		0.19
ClinPred		0.0017	T
GERP RS		-0.90
PromoterAI		0.014	Neutral
Varity_R		0.10
gMVP		0.40
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10794537; hg19: chr4-980971; COSMIC: COSV56101815; COSMIC: COSV56101815;