rs113993949

Positions:

• chrX-149503477-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000202.8(IDS):​c.253G>A​(p.Ala85Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A85S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.43

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-149503477-C-T is Pathogenic according to our data. Variant chrX-149503477-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149503477-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8	c.253G>A	p.Ala85Thr	missense_variant	3/9	ENST00000340855.11	NP_000193.1
IDS	NM_006123.5	c.253G>A	p.Ala85Thr	missense_variant	3/8		NP_006114.1
IDS	NM_001166550.4	c.15-32G>A		intron_variant			NP_001160022.1
IDS	NR_104128.2	n.422G>A		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.253G>A	p.Ala85Thr	missense_variant	3/9	1	NM_000202.8	ENSP00000339801	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
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_Moderate), 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) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 29, 2023	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PP1 supporting, PP3 supporting, PP4 -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	May 16, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2018	Variant summary: IDS c.253G>A (p.Ala85Thr) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 169233 control chromosomes (gnomAD). c.253G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome)(Alkhzouz_2016, Amartino_2014, Dvorakova_2017, Kosuga_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Alkhzouz_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 10, 2022	- -
Affects, no assertion criteria provided	research	Pediatrics, All India Institute of Medical Sciences, New Delhi	Apr 01, 2014	The change c.253G>A, (p.A85T) was found to be a known missense variant, where the non-polar amino acid Alanine at 85 position was substituted with another polar amino acid Threonine. Uttarilli et al., described it in MPS II patients with attenuated phenotype from Kerala and Karnataka (Uttarilli et al.,2016). Rathmann et al., described A85T initially in one European MPS-II patients with attenuated phenotype (Rathmann et al.,1982). In our study, it was detected in the hemizygous condition in patients with MPS-II attenuated phenotype, hails from from the state of UP and Bihar, India. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 24, 2022	ClinVar contains an entry for this variant (Variation ID: 92617). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IDS function (PMID: 17091340). 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. This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 8940265, 25976201, 26762690, 31877959). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 85 of the IDS protein (p.Ala85Thr). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 05, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;D;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L;L;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.010	D;D;T;.
Polyphen		1.0	D;D;D;.
Vest4		0.67
MutPred		0.92		Gain of phosphorylation at A85 (P = 0.0615);Gain of phosphorylation at A85 (P = 0.0615);Gain of phosphorylation at A85 (P = 0.0615);Gain of phosphorylation at A85 (P = 0.0615);
MVP		0.99
MPC		2.2
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.83
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs113993949; hg19: chrX-148585007; COSMIC: COSV100558243; COSMIC: COSV100558243;