4-1004286-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000203.5(IDUA):c.1855C>T(p.Arg619Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,610,614 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

IDUA
NM_000203.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.378

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 18 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 23 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-1004286-C-T is Pathogenic according to our data. Variant chr4-1004286-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 280976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.1855C>T	p.Arg619Ter	stop_gained	14/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.1855C>T	p.Arg619Ter	stop_gained	14/14	2	NM_000203.5	P1	P35475-1
IDUA	ENST00000247933.9 linkuse as main transcript	c.1855C>T	p.Arg619Ter	stop_gained	14/14	1		P1	P35475-1
IDUA	ENST00000514698.5 linkuse as main transcript	n.1966C>T		non_coding_transcript_exon_variant	11/11	5
IDUA	ENST00000652070.1 linkuse as main transcript	n.1911C>T		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151986

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000807

AC:

AN:

247950

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134718

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1458628

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725780

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151986

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74234

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000240

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Arg619Ter variant in IDUA has been reported in at least 12 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 11735025, 27146977) and has been identified in 0.001% (1/112290) of European (non-Finnish) chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965031). 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: 280976) as pathogenic by EGL Genetic Diagnostics and Counsyl. This nonsense variant leads to a premature termination codon at position 619. This alteration occurs in 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 phenotype of individuals homozygous for this variant is highly specific for MPS based on very low alpha-L-iduronidase activity consistent with disease (PMID: 27146977). The presence of this variant in 6 affected homozygotes and in combination with reported pathogenic variants in at least 5 individuals with MPS increases the likelihood that the p.Arg619Ter variant is pathogenic (VariationID: 11908, 11909, 11910, 496834; PMID: 28752568, 11735025, 27146977). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it results in a truncated protein, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PM2, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 09, 2023	This sequence change creates a premature translational stop signal (p.Arg619*) in the IDUA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the IDUA protein. This variant is present in population databases (rs121965031, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (MPS I) (PMID: 11735025, 27146977, 28752568). ClinVar contains an entry for this variant (Variation ID: 280976). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2018	Variant summary: IDUA c.1855C>T (p.Arg619X) 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 119432 control chromosomes (ExAC). The variant, c.1855C>T, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 with limited to no IDUA enzyme activity detected (Beesley_2001, Uttarilli_2016). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite 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.	Jul 22, 2020	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 22, 2016

- -

Hurler syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.62

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

D;D;D

Vest4

0.81

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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