dbSNP rs794726877: IDUA:p.Gly51Asp (chr4-987236-G-A) – ACMG Classification: Pathogenic (6 pts)

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3PM2_SupportingPP4PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5(IDUA):c.152G>A variant in IDUA is predicted to result in a missense substitution, p.Gly51Asp. This variant has been reported in 9-13% of Italian MPS1 alleles (PMID:9427149, 12203999, 21394825), and has been identified in patients from other European countries as well as Iran, Egypt, and India (PMID:19839758, 31298590, 33301762). When reported, the diagnosis confirmed by deficiency of iduronidase activity (PMID:7951228, 9427149, 12203999, 21394825) including one patient with detailed clinical features and residual enzyme activity values provided (PMID:33301762) (PP4). At least 7 patients are homozygous for the variant (PMIDs: 9427149, 12203999, 19839758, 21394825, 31298590, 33301762). In addition, at least 6 patients are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, all phase unknown, including c.208C>T (p.Gln70Ter) (2 patients, PMID:12203999), c.1205G>A (p.Trp402Ter) (PMID:7951228), and c.1598C>G (p.Pro533Arg) (at least 2 patients, PMID:9427149, 12203999, 21394825), and c.1163delC (PMID:12203999) (PM3_Very Strong). Further patients have been reported who are compound heterozygous for the variant but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PMID:9427149, 12203999, 21394825). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002447 (2/81730 alleles) in the South Asian 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 0.914 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 (PP3_Moderate). SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 193061). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274902/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 2.82

Publications

19 publications found

Variant links:

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 links:

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

SLC26A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 6 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IDUA	NM_000203.5	MANE Select	c.152G>A	p.Gly51Asp	missense	Exon 1 of 14	NP_000194.2
SLC26A1	NM_134425.4		c.576+3892C>T		intron	N/A	NP_602297.1
IDUA	NR_110313.1		n.240G>A		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.152G>A	p.Gly51Asp	missense	Exon 1 of 14	ENSP00000425081.2
IDUA	ENST00000247933.9	TSL:1	c.152G>A	p.Gly51Asp	missense	Exon 1 of 14	ENSP00000247933.4
SLC26A1	ENST00000398520.6	TSL:1	c.576+3892C>T		intron	N/A	ENSP00000381532.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000915

AC:

AN:

109252

AF XY:

0.0000165

show subpopulations

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:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000515

AC:

AN:

1360306

Hom.:

Cov.:

AF XY:

0.00000596

AC XY:

AN XY:

671186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28404

American (AMR)

AF:

0.00

AC:

AN:

34084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24284

East Asian (EAS)

AF:

0.00

AC:

AN:

32666

South Asian (SAS)

AF:

0.0000260

AC:

AN:

76894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.00000467

AC:

AN:

1069818

Other (OTH)

AF:

0.00

AC:

AN:

56730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis type 1 (6)

not provided (2)

Hurler syndrome (1)

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.7

PhyloP100

2.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.79

MutPred

0.82

Gain of glycosylation at T56 (P = 0.0787)

MVP

1.0

MPC

0.87

ClinPred

1.0

GERP RS

3.6

PromoterAI

0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.95

gMVP

0.92

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over