chrX-149490314-C-A

Position:

• chrX-149490314-C-A

Variant summary

Our verdict is Pathogenic. Variant got 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin 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

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 12 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 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 [Likely_pathogenic]. Clinvar id is 2737383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius 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 id is 457353.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.1006G>T	p.Gly336Trp	missense_variant, splice_region_variant	7/9	ENST00000340855.11
IDS	NM_001166550.4	c.736G>T	p.Gly246Trp	missense_variant, splice_region_variant	7/9
IDS	NM_006123.5	c.1006G>T	p.Gly336Cys	missense_variant, splice_region_variant	7/8
IDS	NR_104128.2	n.1305G>T		splice_region_variant, non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.1006G>T	p.Gly336Trp	missense_variant, splice_region_variant	7/9	1	NM_000202.8	P1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2018

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
MutationTaster	Benign	1.0	D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557338581; hg19: chrX-148571845;