rs781997631

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000202.8(IDS):c.191T>C(p.Ile64Thr) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I64N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

IDS
NM_000202.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.34

Publications

1 publications found

Variant links:

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]

IDS Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 2
Inheritance: XL, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia, Myriad Women’s Health
mucopolysaccharidosis type 2, attenuated form
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
mucopolysaccharidosis type 2, severe form
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

IDS links:

ENSG00000241489 (HGNC:):

ENSG00000241489 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000202.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-149504206-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 221222.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8 link	c.191T>C	p.Ile64Thr	missense_variant	Exon 2 of 9	ENST00000340855.11	NP_000193.1	P22304-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11 link	c.191T>C	p.Ile64Thr	missense_variant	Exon 2 of 9	1	NM_000202.8	ENSP00000339801.6		P22304-1
ENSG00000241489	ENST00000651111.1 link	c.-215-3169T>C		intron_variant	Intron 8 of 13			ENSP00000498395.1		B3KWA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000561

AC:

AN:

178358

AF XY:

0.0000158

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.13e-7

AC:

AN:

1095416

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26365

American (AMR)

AF:

0.00

AC:

AN:

35052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19324

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840365

Other (OTH)

AF:

0.00

AC:

AN:

45990

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: IDS c.191T>C (p.Ile64Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 5.6e-06 in 178358 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.191T>C in individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 3527560). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.191T>C (p.I64T) alteration is located in exon 2 (coding exon 2) of the IDS gene. This alteration results from a T to C substitution at nucleotide position 191, causing the isoleucine (I) at amino acid position 64 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.78

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

D;T;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;H;.;.

PhyloP100

8.3

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;T;.

Polyphen

0.99

D;D;D;.

Vest4

0.82

MutPred

0.82

Loss of stability (P = 6e-04);Loss of stability (P = 6e-04);Loss of stability (P = 6e-04);Loss of stability (P = 6e-04);

MVP

1.0

MPC

2.1

ClinPred

0.99

GERP RS

4.9

Varity_R

0.95

gMVP

0.99

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over