4-1004292-C-T

Position:

chr4-1004292-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000203.5(IDUA):c.1861C>T(p.Arg621*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,610,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

IDUA
NM_000203.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-1004292-C-T is Pathogenic according to our data. Variant chr4-1004292-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1861C>T	p.Arg621*	stop_gained	14/14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1861C>T	p.Arg621*	stop_gained	14/14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1861C>T	p.Arg621*	stop_gained	14/14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.1972C>T		non_coding_transcript_exon_variant	11/11	5
IDUA	ENST00000652070.1 link	n.1917C>T		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151964

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248290

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1458876

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Arg621Ter variant in IDUA has been reported in at least 4 individuals with mucopolysaccharidosis (MPS) (PMID: 11735025, 7951228, 27146977, 7550242) and has been identified in 0.014% (5/34554) of Latino chromosomes, 0.003% (1/30604) of South Asian chromosomes and 0.001% (1/112398) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965025). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 11917) as pathogenic by Counsyl, Integrated Genetics, and OMIM. This nonsense variant leads to a premature termination codon at position 621. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in 1 affected homozygote and in combination with reported pathogenic variants in 2 individuals with MPS increases the likelihood that the p.Arg621Ter variant is pathogenic (VariationID: 11908, 550799; PMID: 11735025, 7951228, 27146977). The phenotype of an individual compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1% of normal consistent with disease (PMID: 23786846). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that the variant will cause loss of function, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of an individual with this variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PM2_supporting, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2024	This sequence change creates a premature translational stop signal (p.Arg621) in the IDUA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the IDUA protein. This variant is present in population databases (rs121965025, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type 1 (PMID: 7550242, 7951228, 21394825, 23786846, 27146977, 28752568). ClinVar contains an entry for this variant (Variation ID: 11917). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the IDUA protein in which other variant(s) (p.Trp626) have been determined to be pathogenic (PMID: 19396826, 21462124, 28752568). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Aug 05, 2020	This nonsense variant is found in exon 14 of 14 and is predicted to result in the disruption of the final 33 amino acids of the protein. This variant has been previously reported as compound heterozygous or homozygous change in patients with Mucopolysaccharidosis type I (PMID: 7951228, 27146977, 23786846, 21394825). Functional characterization of the variant indicates that it reduces enzyme activity to less than 10% residual activity (PMID: 23786846). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (7/248290) and thus is presumed to be rare. Based on the available evidence, the c.1861C>T (p.Arg621Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2018	Variant summary: IDUA c.1861C>T (p.Arg621X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.5e-05 in 243934 control chromosomes (gnomAD and publications). The variant, c.1861C>T, has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (Uttarilli_2016, Bunge_1994, Oussorena_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Uttarilli_2016). The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 21, 2021	- -

Hurler syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 30, 2017	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 30, 2022

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

Vest4

0.80

GERP RS

4.7

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

Other links and lift over