NM_000202.8:c.754_767delGATCCCGAGGTCCC

Variant names:

• chrX-149496457-AGGGACCTCGGGATC-A
• rs869025305
• NM_000202.8:c.754_767delGATCCCGAGGTCCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000202.8(IDS):​c.754_767delGATCCCGAGGTCCC​(p.Asp252fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.56
• Publications: 1 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-149496457-AGGGACCTCGGGATC-A is Pathogenic according to our data. Variant chrX-149496457-AGGGACCTCGGGATC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 221974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000202.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	NM_000202.8	MANE Select	c.754_767delGATCCCGAGGTCCC	p.Asp252fs	frameshift	Exon 6 of 9	NP_000193.1
	IDS	NM_001166550.4		c.484_497delGATCCCGAGGTCCC	p.Asp162fs	frameshift	Exon 6 of 9	NP_001160022.1
	IDS	NM_006123.5		c.754_767delGATCCCGAGGTCCC	p.Asp252fs	frameshift	Exon 6 of 8	NP_006114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.754_767delGATCCCGAGGTCCC	p.Asp252fs	frameshift	Exon 6 of 9	ENSP00000339801.6
	IDS	ENST00000370441.8	TSL:1	c.754_767delGATCCCGAGGTCCC	p.Asp252fs	frameshift	Exon 6 of 8	ENSP00000359470.4
	ENSG00000241489	ENST00000651111.1		c.121_134delGATCCCGAGGTCCC	p.Asp41fs	frameshift	Exon 11 of 14	ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2

Jun 07, 2024

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Null variant (PVS1_VeryStrong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Strong)

Oct 18, 2015

MOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Pathogenic variation identified in a Hunter syndrome male patient without I2S evaluation. He presents mental retardation, but no seizures, nor hydrocephaly.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs869025305; hg19: chrX-148577988;