rs6831280

Variant names:

• chr4-1002377-G-A
• rs6831280
• NM_000203.5:c.1081G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1002377-G-A
• chr4-1002377-G-C

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.1081G>A variant in IDUA is a missense variant predicted to cause substitution of alanine by threonine at amino acid 361 (p.Ala361Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (27037/90842 alleles; 4256 homozygotes; Grpmax Filtering AF 95% confidence = 0.2947) in the South Asian 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: 92624). 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/CA145865/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.17 (2341 hom., cov: 34)
  • Exomes 𝑓: 0.16 (20394 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign reviewed by expert panel B:14 O:1
• Conservation: PhyloP100: 1.14
• Publications: 55 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 -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.1081G>A	p.Ala361Thr	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.685G>A	p.Ala229Thr	missense_variant	Exon 7 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.1081G>A	p.Ala361Thr	missense_variant	Exon 8 of 12		XP_047271606.1
IDUA	NR_110313.1	n.1169G>A		non_coding_transcript_exon_variant	Exon 8 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1081G>A	p.Ala361Thr	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1081G>A	p.Ala361Thr	missense_variant	Exon 8 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1188G>A		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1	n.1137G>A		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26116 AN: 152110 Hom.: 2344 Cov.: 34

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.172 AC: 41988 AN: 243470 AF XY: 0.181

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.161 AC: 234399 AN: 1458830 Hom.: 20394 Cov.: 35 AF XY: 0.165 AC XY: 119589 AN XY: 725586

African (AFR) AF: 0.220 AC: 7368 AN: 33428

American (AMR) AF: 0.0834 AC: 3709 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3987 AN: 26062

East Asian (EAS) AF: 0.171 AC: 6784 AN: 39580

South Asian (SAS) AF: 0.298 AC: 25596 AN: 86020

European-Finnish (FIN) AF: 0.152 AC: 7943 AN: 52382

Middle Eastern (MID) AF: 0.202 AC: 1162 AN: 5764

European-Non Finnish (NFE) AF: 0.151 AC: 167755 AN: 1110850

Other (OTH) AF: 0.167 AC: 10095 AN: 60290

GnomAD4 genome AF: 0.172 AC: 26114 AN: 152224 Hom.: 2341 Cov.: 34 AF XY: 0.172 AC XY: 12793 AN XY: 74430

African (AFR) AF: 0.212 AC: 8796 AN: 41522

American (AMR) AF: 0.122 AC: 1859 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1034 AN: 5170

South Asian (SAS) AF: 0.299 AC: 1441 AN: 4822

European-Finnish (FIN) AF: 0.144 AC: 1527 AN: 10616

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10305 AN: 68006

Other (OTH) AF: 0.178 AC: 377 AN: 2114

Alfa AF: 0.162 Hom.: 3670

Bravo AF: 0.168

TwinsUK AF: 0.166 AC: 614

ALSPAC AF: 0.159 AC: 611

ESP6500AA AF: 0.200 AC: 880

ESP6500EA AF: 0.158 AC: 1360

ExAC AF: 0.179 AC: 21632

Asia WGS AF: 0.248 AC: 868 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Nov 02, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1 Benign:4 Other:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.1081G>A variant in IDUA is a missense variant predicted to cause substitution of alanine by threonine at amino acid 361 (p.Ala361Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2976 (27037/90842 alleles; 4256 homozygotes; Grpmax Filtering AF 95% confidence = 0.2947) in the South Asian 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: 92624). 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. -

Mar 29, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Pseudodeficiency variants -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28649516, 29801497, 26256109, 27884173, 24875751) -

Jan 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hurler syndrome Benign:1

May 18, 2021

Pars Genome 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	0.067
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.94
DANN	Benign	0.83
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.81	T;.
MetaRNN	Benign	0.0061	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.2	N;.
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;.
Vest4		0.037
MPC		0.18
ClinPred		0.0033	T
GERP RS		-6.4
Varity_R		0.066
gMVP		0.38
Mutation Taster		=95/5	polymorphism (auto)

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: rs6831280; hg19: chr4-996165; COSMIC: COSV56101293; COSMIC: COSV56101293;