4-1002767-G-C

Variant names:

• chr4-1002767-G-C
• rs11934801
• NM_000203.5:c.1225G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000203.5(IDUA):​c.1225G>C​(p.Gly409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,481,578 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G409E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (53 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 0.768
• Publications: 16 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: ClinGen, Myriad Women’s Health
• Scheie syndrome

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

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

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030357838).
• BP6: Variant 4-1002767-G-C is Benign according to our data. Variant chr4-1002767-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92627.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1225G>C	p.Gly409Arg	missense_variant	Exon 9 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.829G>C	p.Gly277Arg	missense_variant	Exon 8 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.1225G>C	p.Gly409Arg	missense_variant	Exon 9 of 12		XP_047271606.1
IDUA	NR_110313.1	n.1313G>C		non_coding_transcript_exon_variant	Exon 9 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1225G>C	p.Gly409Arg	missense_variant	Exon 9 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2757 AN: 150922 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00924

Gnomad EAS AF: 0.0163

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.000487

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00358 AC: 313 AN: 87312 AF XY: 0.00261

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00813

Gnomad EAS exome AF: 0.0148

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000714

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00204 AC: 2720 AN: 1330546 Hom.: 53 Cov.: 34 AF XY: 0.00176 AC XY: 1155 AN XY: 655764

African (AFR) AF: 0.0561 AC: 1507 AN: 26860

American (AMR) AF: 0.00509 AC: 150 AN: 29492

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 165 AN: 23574

East Asian (EAS) AF: 0.0103 AC: 305 AN: 29682

South Asian (SAS) AF: 0.000137 AC: 10 AN: 73162

European-Finnish (FIN) AF: 0.0000299 AC: 1 AN: 33404

Middle Eastern (MID) AF: 0.00382 AC: 15 AN: 3930

European-Non Finnish (NFE) AF: 0.000230 AC: 243 AN: 1055108

Other (OTH) AF: 0.00586 AC: 324 AN: 55334

GnomAD4 genome AF: 0.0184 AC: 2775 AN: 151032 Hom.: 72 Cov.: 33 AF XY: 0.0175 AC XY: 1292 AN XY: 73836

African (AFR) AF: 0.0593 AC: 2434 AN: 41054

American (AMR) AF: 0.0106 AC: 161 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00924 AC: 32 AN: 3462

East Asian (EAS) AF: 0.0163 AC: 83 AN: 5082

South Asian (SAS) AF: 0.000839 AC: 4 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10406

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000487 AC: 33 AN: 67718

Other (OTH) AF: 0.0128 AC: 27 AN: 2108

Alfa AF: 0.00175 Hom.: 3

Bravo AF: 0.0206

ESP6500AA AF: 0.0278 AC: 66

ESP6500EA AF: 0.000437 AC: 2

ExAC AF: 0.00388 AC: 70

Asia WGS AF: 0.00785 AC: 27 AN: 3452

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Mar 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IDUA c.1225G>C (p.Gly409Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 118354 control chromosomes (gnomAD), predominantly at a frequency of 0.057 within the African or African-American subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Nine ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, three as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign. -

Mar 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1 Benign:4

Apr 23, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly409Arg variant has not been previously reported in individuals with mucopolysaccharidosis (MPS) but has been identified in 5.567% (555/9810) of African chromosomes, including 16 homozygotes, and 3 additional homozygotes in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs11934801). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as benign by Invitae, EGL Genetic Diagnostics, and Children's Mercy Hospital and Clinics, likely benign by Illumina, and a VUS by the Children's Hospital of Philadelphia and the NUS Institute of Precision Medicine (Variation ID: 92627). It has also been reported in the heterozygous state and described as a pseudodeficiency allele in an unaffected individual from newborn screening, suggesting that this variant is not pathogenic for disease (PMID: 31133280). In summary, this variant meets criteria to be classified as benign for mucopolysaccharidosis in an autosomal recessive manner based on the high frequency of the variant in the general population. ACMG/AMP Criteria applied: BA1, BS2 (Richards 2015). -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Sep 08, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 04, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Appears to be a hypomorphic allele. Functional studies indicate that this variant reduces protein activity to 61% (Bach et al., 1993), which is not in the pathogenic range for this enzyme.; This variant is associated with the following publications: (PMID: 30709774, 31133280, 28676128, 27335677, 8328452, 21228398) -

Hurler syndrome Uncertain:1 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T;.
MetaRNN	Benign	0.030	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L;.
PhyloP100		0.77
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.088	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.95	P;.
Vest4		0.24
MVP		0.99
MPC		0.32
ClinPred		0.027	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.59
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11934801; hg19: chr4-996555;