VCV000193062.20 - ClinVar

NM_000203.5(IDUA):c.53T>C (p.Leu18Pro)

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.

(7)

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.

Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000203.5(IDUA):c.53T>C (p.Leu18Pro)

Variation ID: 193062 Accession: VCV000193062.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.3 4: 987137 (GRCh38) [ NCBI UCSC ] 4: 980925 (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	Apr 2, 2018	Feb 20, 2024	Dec 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000203.5:c.53T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000194.2:p.Leu18Pro	missense
NM_134425.4:c.576+3991A>G		intron variant
NR_110313.1:n.141T>C		non-coding transcript variant
NC_000004.12:g.987137T>C
NC_000004.11:g.980925T>C
NG_008103.1:g.5141T>C
NG_033042.1:g.11300A>G
NG_158244.2:g.337T>C
LRG_1277:g.5141T>C
LRG_1277t1:c.53T>C	LRG_1277p1:p.Leu18Pro
	P35475:p.Leu18Pro

... more HGVS ... less HGVS

Protein change

L18P

Other names

Canonical SPDI

NC_000004.12:987136:T: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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA238566 UniProtKB: P35475#VAR_072367 dbSNP: rs794726878 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.
IDUA		-	-	GRCh38 GRCh37	1391	2155
SLC26A1		-	-	GRCh38 GRCh37	3	766

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.
Hurler syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 11, 2023	RCV000592086.14
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 13, 2023	RCV000724295.20
Mucopolysaccharidosis type 1	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 2, 2023	RCV001248919.16

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 (May 22, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Hurler syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800112.1 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Publications: PubMed (2) PubMed: 25557439‚ 25256405
Likely pathogenic (Jan 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Mucopolysaccharidosis type 1 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001422681.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022	Publications: PubMed (2) PubMed: 25557439‚ 25256405 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8098c57c-e713-4d8f-821c-0a0ee24a72b1 Comment: The p.Leu18Pro variant in IDUA has been reported in 5 individuals with mucopolysaccharidosis, MSP (PMID: 25256405, 25557439) and was absent from large population studies and … (more) The p.Leu18Pro variant in IDUA has been reported in 5 individuals with mucopolysaccharidosis, MSP (PMID: 25256405, 25557439) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 2 individuals with MSP increases the likelihood that the p.Leu18Pro variant is pathogenic (VariationID: 11909, 11908; PMID: 25256405, 25557439). The phenotype of individuals homozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 25256405). The p.Leu18Pro variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 25256405). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM1, PM2_supporting, PP4 (Richards 2015). (less)
Uncertain significance (May 13, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001990726.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25256405, 25557439) (less)
Likely pathogenic (Apr 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016668.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001587516.4 First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 25256405‚ 25557439‚ 31194252 Comment: This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 18 of the IDUA protein (p.Leu18Pro). … (more) This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 18 of the IDUA protein (p.Leu18Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 25256405, 25557439, 31194252). ClinVar contains an entry for this variant (Variation ID: 193062). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IDUA protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 22, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000700757.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 25256405 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Mar 11, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hurler syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136673.2 First in ClinVar: Jan 09, 2020 Last updated: Mar 18, 2023

Comment:

The p.Leu18Pro variant in IDUA has been reported in 5 individuals with mucopolysaccharidosis, MSP (PMID: 25256405, 25557439) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 2 individuals with MSP increases the likelihood that the p.Leu18Pro variant is pathogenic (VariationID: 11909, 11908; PMID: 25256405, 25557439). The phenotype of individuals homozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 25256405). The p.Leu18Pro variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 25256405). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM1, PM2_supporting, PP4 (Richards 2015).

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25256405, 25557439)

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 18 of the IDUA protein (p.Leu18Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 25256405, 25557439, 31194252). ClinVar contains an entry for this variant (Variation ID: 193062). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IDUA protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

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
Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry.	Clarke LA	Clinical genetics	2019	PMID: 31194252
Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses.	Utz JR	Molecular genetics and metabolism	2015	PMID: 25557439
p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients.	Pasqualim G	Clinical genetics	2015	PMID: 25256405
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8098c57c-e713-4d8f-821c-0a0ee24a72b1	-	-	-	-

Text-mined citations for rs794726878 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000203.5(IDUA):c.53T>C (p.Leu18Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs794726878 ...