rs864622772

Positions:

• chrX-149483006-G-A
• chrX-149483006-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000202.8(IDS):​c.1393C>T​(p.Gln465*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.79

Genes affected

IDS (HGNC:5389): (iduronate 2-sulfatase) This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ENSG00000241489 (HGNC:):

ACMG classification

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 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-149483006-G-A is Pathogenic according to our data. Variant chrX-149483006-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 221202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149483006-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8	c.1393C>T	p.Gln465*	stop_gained	9/9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.1123C>T	p.Gln375*	stop_gained	9/9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1393C>T	p.Gln465*	stop_gained	9/9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.760C>T	p.Gln254*	stop_gained	14/14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.760C>T	p.Gln254*	stop_gained	9/9	2		ENSP00000477056.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 19, 2018	This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with mucopolysaccharidosis type II (PMID: 8830188, 17063374, Invitae). ClinVar contains an entry for this variant (Variation ID: 221202). Other truncations (p.Met488Serfs*11, p.Tyr523Leufs*6 and p.Leu530Phefs*8) that lie downstream of this variant have been reported in individuals affected with mucopolysaccharidosis type II (PMID: 27246110, 8940265, 17284421). For these reasons, this variant has been classified as Pathogenic. This sequence change results in a premature translational stop signal in the IDS gene (p.Gln465*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acids of the IDS protein. -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	Oct 30, 2013	- -
Pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	Null variant (PVS1_Strong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Strong) -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2022

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 85 amino acids are lost, and other variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25681085, 17063374, 9950361, 8830188, 27896113) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.75
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs864622772; hg19: chrX-148564537; COSMIC: COSV100558107; COSMIC: COSV100558107;