4-987085-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM3PM2_SupportingPP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1A>G (p.Met1?) variant in IDUA is predicted to cause an N-terminal truncated or absent protein by altering the start codon of the coding sequence. The next in-frame ATG is at position 133. If that ATG is used as a start signal, the lysosomal signal sequence (amino acids 1-27) would be lost (https://www.uniprot.org/uniprotkb/P35475/entry) (PVS1). Two patients with severe MPS1 (Hurler syndrome) are reported to be homozygous for the variant (PMID:27146977, 28752568) (PM3). One patient, from India, had clinical features consistent with a severe presentation of MPS 1 including dysostosis multiplex, coarse facial features, cardiomegaly, and intellectual disability, as well as documented deficient activity of IDUA in leukocytes (PMID:27146977), while a second patient, from Spain, was reported to have a confirmed diagnosis based on IDUA deficiency (PMID:21394825) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 8.893e-7 (1/1124490) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Of note, other variants that abolish the start ATG have been identified in individuals with mucopolysaccharidosis type 1 (c.1A>C, ClinVar Variation ID: 550458; c.2T>C, ClinVar Variation ID: 639529). There is a ClinVar entry for c.1A>G (Variation ID:1323098). In summary, this variant, c.1A>G (p.Met1?) 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 Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, 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/CA355945206/MONDO:0001586/091

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

IDUA
NM_000203.5 start_lost

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: -1.98

Publications

0 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 links:

DGKQ (HGNC:2856): (diacylglycerol kinase theta) The protein encoded by this gene contains three cysteine-rich domains, a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. It is localized in the speckle domains of the nucleus, and mediates the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. [provided by RefSeq, Jul 2008]

DGKQ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

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 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.51e-7

AC:

AN:

1332042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

659440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27084

American (AMR)

AF:

0.00

AC:

AN:

30198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22438

East Asian (EAS)

AF:

0.00

AC:

AN:

29388

South Asian (SAS)

AF:

0.00

AC:

AN:

74140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3820

European-Non Finnish (NFE)

AF:

9.47e-7

AC:

AN:

1056520

Other (OTH)

AF:

0.00

AC:

AN:

54412

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:2

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000203.5:c.1A>G (p.Met1?) variant in IDUA is predicted to cause an N-terminal truncated or absent protein by altering the start codon of the coding sequence. The next in-frame ATG is at position 133. If that ATG is used as a start signal, the lysosomal signal sequence (amino acids 1-27) would be lost (https://www.uniprot.org/uniprotkb/P35475/entry) (PVS1). Two patients with severe MPS1 (Hurler syndrome) are reported to be homozygous for the variant (PMID: 27146977, 28752568) (PM3). One patient, from India, had clinical features consistent with a severe presentation of MPS 1 including dysostosis multiplex, coarse facial features, cardiomegaly, and intellectual disability, as well as documented deficient activity of IDUA in leukocytes (PMID: 27146977), while a second patient, from Spain, was reported to have a confirmed diagnosis based on IDUA deficiency (PMID: 21394825) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 8.893e-7 (1/1124490) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Of note, other variants that abolish the start ATG have been identified in individuals with mucopolysaccharidosis type 1 (c.1A>C, ClinVar Variation ID: 550458; c.2T>C, ClinVar Variation ID: 639529). There is a ClinVar entry for c.1A>G (Variation ID:1323098). In summary, this variant, c.1A>G (p.Met1?) 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 Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the IDUA mRNA. The next in-frame methionine is located at codon 133. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 27146977, 31236806). ClinVar contains an entry for this variant (Variation ID: 1323098). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Apr 08, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.084

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.33

PhyloP100

-2.0

PROVEAN

Benign

-0.70

N;N

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.0

B;.

Vest4

0.76

MutPred

0.99

Loss of glycosylation at P6 (P = 0.0238);Loss of glycosylation at P6 (P = 0.0238);

MVP

0.86

ClinPred

0.64

GERP RS

-2.0

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.72

Mutation Taster

=6/194

disease causing

(source)

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

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.

4-987085-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over