rs1557338581

Variant names:

• chrX-149490314-C-A
• rs1557338581
• NM_000202.8:c.1006G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000202.8(IDS):​c.1006G>T​(p.Gly336Trp) variant causes a missense, splice region 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. 12/21 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G336E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS NM_000202.8 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.31
• Publications: 0 publications found

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

ENSG00000241489 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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-149487098-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2737383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-149490314-C-A is Pathogenic according to our data. Variant chrX-149490314-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 457353.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.1006G>T	p.Gly336Trp	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.736G>T	p.Gly246Trp	missense_variant, splice_region_variant	Exon 7 of 9		NP_001160022.1
IDS	NM_006123.5	c.1006G>T	p.Gly336Cys	missense_variant, splice_region_variant	Exon 7 of 8		NP_006114.1
IDS	NR_104128.2	n.1305G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1006G>T	p.Gly336Trp	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.373G>T	p.Gly125Trp	missense_variant, splice_region_variant	Exon 12 of 14			ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:1

Jan 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Likely Pathogenic. A different variant affecting this nucleotide (c.1006G>C) has been shown to disrupt RNA splicing and determined as likely pathogenic (PMID: 17063374, Invitae). This suggests that codon 336 is important for normal RNA processing and protein function, and that other variants at this position, such as c.1006G>T, may also be pathogenic. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) and according to multiple splice site algorithms this particular variant may affect splicing. These predictions have not been confirmed by published functional studies. Two different variant affecting this nucleotide, c.1006G>C and c.1006G>A (both cause Gly to Arg change at codon 336) have been reported in individuals affected with Hunter disease (PMID: 17063374, 9266380, 8830188). In addition, other IDS missense changes affecting the same codon c.1007G>A (p.Gly336Glu) and c.1007G>T (p.Gly336Val) have also been reported in affected individuals (PMID: 24125893, 9660053). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a IDS-related disease. This sequence change replaces glycine with tryptophan at codon 336 of the IDS protein (p.Gly336Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant also falls at the last nucleotide of exon 7 of the IDS coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	37
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.2	D
PhyloP100		7.3
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.94		Loss of disorder (P = 0.0396);
MVP		0.96
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
Mutation Taster		=195/105	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.90		Position offset: -22

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

Other links and lift over

dbSNP: rs1557338581; hg19: chrX-148571845;