Variant 4-1004391-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP5_Moderate

The NM_000203.5(IDUA):c.1960T>G(p.Ter654Glyext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IDUA
NM_000203.5 stop_lost

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:3O:1

Conservation

PhyloP100: 0.123

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:

IDUA (HGNC:):

IDUA links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Stoplost variant in NM_000203.5 Downstream stopcodon found after 666 codons.

PP5

Variant 4-1004391-T-G is Pathogenic according to our data. Variant chr4-1004391-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 11920.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.1960T>G	p.Ter654Glyext*?	stop_lost	14/14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.1960T>G	p.Ter654Glyext*?	stop_lost	14/14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 linkuse as main transcript	c.1960T>G	p.Ter654Glyext*?	stop_lost	14/14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 linkuse as main transcript	n.2071T>G		non_coding_transcript_exon_variant	11/11	5
IDUA	ENST00000652070.1 linkuse as main transcript	n.2016T>G		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457954

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725374

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:2Other:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 06, 2024	The NM_000203.5:c.1960T>G in IDUA is a stop-loss variant, predicted to alter the stop codon (p.Ter654Gly), resulting in an increase in the length of the protein (PM1). One patient with "Hurler-Scheie" syndrome, who is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909), has been reported. The variants were confirmed to be in trans (PMID: 7550232) (PM3; insufficient evidence to apply PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 8.475e-7 (1/1179958 alleles) 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). When the variant was expressed in COS cells, the intracellular activity of IDUA was low (negative control 1.3 (U/mg cell protein, wild type 14.5 (U/mg cell protein, variant 2.5 (U/mg cell protein), approximately 10% wild type ( PMID: 7550232). This is higher than the LD VCEP's threshold for IDUA activity for PS3_Supporting (<2%), therefore, PS3 was not applied. Other IDUA stop loss variants have been reported in patients with MPS1. One of these variants, c.1960T>C (p.Ter654Arg) (Bertola et al, PMID: 21394825; Ngiwsara et al, PMID: 29282708), has been classified as likely pathogenic by the ClinGen LD VCEP (PM5_Supporting). The other variants are c.1961A>T (p.Ter654Cys) ((Bach et al, 1993, PMID: 8328452) and c.1960T>A (p.Ter654Arg) (Thomas et al, PMID: 33301762). In summary, this variant meets the criteria to be classified as likely 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): PM4, PM3, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -
not provided, no classification provided	literature only	GeneReviews	-	Variant causes attenuated MPS I; predict extension of α-L-iduronidase at the carboxyl end that may change conformation and/or stability of enzyme. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2020	This variant results in an extension of the IDUA protein. Other variant(s) that result in a similarly extended protein product (p.654Argext) have been determined to be pathogenic (PMID: 29282708, 21394825). This suggests that these extensions are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This sequence change disrupts the translational stop signal of the IDUA mRNA. It is expected to extend the length of the IDUA protein by 55 additional amino acid residues. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with IDUA-related conditions (PMID: 7550232). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11920). This variant has been reported to affect IDUA protein function (PMID: 7550232). -

Mucopolysaccharidosis, MPS-I-H/S

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.30

DANN

Benign

0.50

Eigen

Benign

0.055

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.064

Vest4

0.15

GERP RS

-0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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