rs869025304

Variant names:

• chrX-149500992-AA-CCAGCTATACGG
• rs869025304
• NM_000202.8:c.463_464delTTinsCCGTATAGCTGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000202.8(IDS):​c.463_464delTTinsCCGTATAGCTGG​(p.Phe155ProfsTer12) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F155L) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.58
• 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-149500992-AA-CCAGCTATACGG is Pathogenic according to our data. Variant chrX-149500992-AA-CCAGCTATACGG is described in ClinVar as Pathogenic. ClinVar VariationId is 221973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.463_464delTTinsCCGTATAGCTGG	p.Phe155ProfsTer12	frameshift_variant, missense_variant	Exon 4 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.193_194delTTinsCCGTATAGCTGG	p.Phe65ProfsTer12	frameshift_variant, missense_variant	Exon 4 of 9		NP_001160022.1
IDS	NM_006123.5	c.463_464delTTinsCCGTATAGCTGG	p.Phe155ProfsTer12	frameshift_variant, missense_variant	Exon 4 of 8		NP_006114.1
IDS	NR_104128.2	n.632_633delTTinsCCGTATAGCTGG		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.463_464delTTinsCCGTATAGCTGG	p.Phe155ProfsTer12	frameshift_variant, missense_variant	Exon 4 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.-171_-170delTTinsCCGTATAGCTGG		5_prime_UTR_variant	Exon 9 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 with I2S deficiency. He presents mental retardation, but no seizures, nor hydrocephaly. Pathogenic variation was inherited through a maternal mixed somatic and germline mosaicism. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs869025304; hg19: chrX-148582523;