rs104894853

Positions:

• chrX-149490322-G-A
• chrX-149490322-G-C
• chrX-149490322-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000202.8(IDS):​c.998C>T​(p.Ser333Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 22)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 9.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-149490322-G-A is Pathogenic according to our data. Variant chrX-149490322-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149490322-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.998C>T	p.Ser333Leu	missense_variant	7/9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.728C>T	p.Ser243Leu	missense_variant	7/9		NP_001160022.1
IDS	NM_006123.5	c.998C>T	p.Ser333Leu	missense_variant	7/8		NP_006114.1
IDS	NR_104128.2	n.1297C>T		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.998C>T	p.Ser333Leu	missense_variant	7/9	1	NM_000202.8	ENSP00000339801	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:8 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1992	- -
Affects, no assertion criteria provided	research	Pediatrics, All India Institute of Medical Sciences, New Delhi	Apr 07, 2014	The change c.998C>T (p.S333L) was found to be a missense variant, where the hydroxyl-containing polar neutral amino acid Serine at 333 position was substituted by aliphatic nonpolar neutral amino acid Leucine. It was detected in a hemizygous state in one case with severe phenotype from Haryana, India. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -
Pathogenic, no assertion criteria provided	provider interpretation	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	Apr 16, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 333 of the IDS protein (p.Ser333Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type II (MPS II) (PMID: 1639384, 28543354, 30639582; Invitae). ClinVar contains an entry for this variant (Variation ID: 10487). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects IDS function (PMID: 17091340, 28543354). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	In vitro or in vivo functional studies supportive of a damaging effect (PS3_Strong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.998C>Tp.Ser333Leu in IDS gene has been reported previously in hemizygous state in most of the individuals with mucopolysaccharidosis type II. Experimental studies have shown that this missense change affects IDS function Sukegawa-Hayasaka K, et al., 2006, Vollebregt AAM, et al., 2017. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions.The amino acid Serine at position 333 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Ser333Leu in IDS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2022	Published functional studies with S333L transfected into CHO, HEK293T, and COS-7 cells indicate a severe impairment of protein function (Sukegawa-Hayasaka et al., 2006; Vollebregt et al., 2017; Lin et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16495038, 9921913, 9660053, 27246110, 1639384, 27695081, 30548430, 30639582, 9950361, 27896113, 27883178, 8830188, 28543354, 9875019, 21291454, 21829674, 33676511, 31877959, 34258227, 35144014, 17091340, 24125893) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.5	D;D;.
REVEL	Pathogenic	0.90
Sift	Benign	0.030	D;D;.
Sift4G	Uncertain	0.055	T;T;D
Polyphen		0.99	D;D;.
Vest4		0.94
MutPred		0.94		Loss of disorder (P = 0.0783);Loss of disorder (P = 0.0783);.;
MVP		1.0
MPC		0.27
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.99

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

Other links and lift over

dbSNP: rs104894853; hg19: chrX-148571853;