VCV002230429.3 - ClinVar

NM_000202.8(IDS):c.1406C>G (p.Pro469Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000202.8(IDS):c.1406C>G (p.Pro469Arg)

Variation ID: 2230429 Accession: VCV002230429.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 149482993 (GRCh38) [ NCBI UCSC ] X: 148564524 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Aug 4, 2024	Jun 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000202.8:c.1406C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000193.1:p.Pro469Arg	missense
NM_001166550.4:c.1136C>G	NP_001160022.1:p.Pro379Arg	missense
NC_000023.11:g.149482993G>C
NC_000023.10:g.148564524G>C
NG_011900.3:g.27342C>G

... more HGVS ... less HGVS

Protein change

P469R, P379R

Other names

Canonical SPDI

NC_000023.11:149482992:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
IDS		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	664	1581

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Apr 29, 2021	RCV002717601.2
Mucopolysaccharidosis, MPS-II	Likely pathogenic (1)	criteria provided, single submitter	Jun 7, 2024	RCV004596569.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Apr 29, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003564614.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 7887413‚ 22976768‚ 27246110 Comment: The c.1406C>G (p.P469R) alteration is located in exon 9 (coding exon 9) of the IDS gene. This alteration results from a C to G substitution … (more) The c.1406C>G (p.P469R) alteration is located in exon 9 (coding exon 9) of the IDS gene. This alteration results from a C to G substitution at nucleotide position 1406, causing the proline (P) at amino acid position 469 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the IDS c.1406C>G alteration was not observed, with coverage at this position. This alteration was reported in a patient with MPS II and low iduronate-2-sulfatase enzyme activity in plasma (Pollard, 2013). In addition, two other alterations affecting the same amino acid, p.P469H and p.P469L, were reported in patients with MPS II (Jonsson, 1995; Kosuga, 2016). This amino acid position is highly conserved in available vertebrate species. The p.P469R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Likely pathogenic (Jun 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: literature only	Mucopolysaccharidosis, MPS-II Affected status: yes Allele origin: germline	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova Accession: SCV005089557.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 Comment: Classification method: ACMG Guidelines [PMID:25741868] with modifications	Publications: PubMed (1) PubMed: 22976768 Comment: Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), … (more) Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Strong) (less) Number of individuals with the variant: 1 Sex: male

Comment:

The c.1406C>G (p.P469R) alteration is located in exon 9 (coding exon 9) of the IDS gene. This alteration results from a C to G substitution at nucleotide position 1406, causing the proline (P) at amino acid position 469 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the IDS c.1406C>G alteration was not observed, with coverage at this position. This alteration was reported in a patient with MPS II and low iduronate-2-sulfatase enzyme activity in plasma (Pollard, 2013). In addition, two other alterations affecting the same amino acid, p.P469H and p.P469L, were reported in patients with MPS II (Jonsson, 1995; Kosuga, 2016). This amino acid position is highly conserved in available vertebrate species. The p.P469R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Comment:

Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Strong)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase.	Kosuga M	Molecular genetics and metabolism	2016	PMID: 27246110
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations.	Pollard LM	Journal of inherited metabolic disease	2013	PMID: 22976768
Molecular diagnosis of mucopolysaccharidosis type II (Hunter syndrome) by automated sequencing and computer-assisted interpretation: toward mutation mapping of the iduronate-2-sulfatase gene.	Jonsson JJ	American journal of human genetics	1995	PMID: 7887413

Text-mined citations for this variant ...

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_000202.8(IDS):c.1406C>G (p.Pro469Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...