rs398123258

chr4-1004082-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000203.5(IDUA):c.1799del(p.Ser600Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S600S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.46

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]

ACMG classification

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-1004082-TC-T is Pathogenic according to our data. Variant chr4-1004082-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 92636.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	c.1799del	p.Ser600Ter	frameshift_variant	13/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.1799del	p.Ser600Ter	frameshift_variant	13/14	2	NM_000203.5	P1
IDUA	ENST00000247933.9	c.1799del	p.Ser600Ter	frameshift_variant	13/14	1		P1
IDUA	ENST00000514698.5	n.1910del		non_coding_transcript_exon_variant	10/11	5
IDUA	ENST00000652070.1	n.1855del		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 12, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IDUA protein in which other variant(s) (p.Arg628*) have been determined to be pathogenic (PMID: 11735025, 16435195; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 92636). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis (PMID: 22976768). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser600*) in the IDUA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the IDUA protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2016	Variant summary: The IDUA c.1799delC (p.Ser600Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent IDUA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120794 control chromosomes. This variant has been reported homozygously in one mucopolysaccharidosis patient, and variant showed zero enzyme activity (Pollard_IUDA_IJMD_2013). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123258; hg19: chr4-997870;