VCV000195039.23 - ClinVar

NM_000203.5(IDUA):c.245A>C (p.His82Pro)

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.

(8)

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
Likely pathogenic(1); Uncertain significance(4); Benign(1); Likely benign(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.245A>C (p.His82Pro)

Variation ID: 195039 Accession: VCV000195039.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.3 4: 987895 (GRCh38) [ NCBI UCSC ] 4: 981683 (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	Jun 28, 2015	Oct 8, 2024	Mar 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000203.5:c.245A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000194.2:p.His82Pro	missense
NM_022042.4:c.*938T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_134425.4:c.576+3233T>G		intron variant
NM_213613.4:c.*938T>G		3 prime UTR
NR_110313.1:n.333A>C		non-coding transcript variant
NC_000004.12:g.987895A>C
NC_000004.11:g.981683A>C
NG_008103.1:g.5899A>C
NG_033042.1:g.10542T>G
LRG_1277:g.5899A>C
LRG_1277t1:c.245A>C	LRG_1277p1:p.His82Pro
	P35475:p.His82Pro

... more HGVS ... less HGVS

Protein change

H82P

Other names

Canonical SPDI

NC_000004.12:987894:A: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), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA201510 UniProtKB: P35475#VAR_003353 dbSNP: rs794727239 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	1390	2153
SLC26A1		-	-	GRCh38 GRCh37	3	765

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.
not specified	Likely benign (1)	criteria provided, single submitter	Jun 19, 2014	RCV000175552.4
Hurler syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 28, 2019	RCV000664739.4
Mucopolysaccharidosis type 1	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 13, 2023	RCV000779453.14
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Mar 27, 2024	RCV003129795.4

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.
Uncertain significance (Jan 06, 2017)	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: SCV000788747.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 12203999‚ 8401515
Uncertain significance (Oct 13, 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: SCV001420326.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 8401515 Comment: This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 82 of the IDUA protein (p.His82Pro). … (more) This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 82 of the IDUA protein (p.His82Pro). This variant is present in population databases (rs794727239, gnomAD 0.002%). This missense change has been observed in individual(s) with MPS I (PMID: 8401515). ClinVar contains an entry for this variant (Variation ID: 195039). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely pathogenic (Mar 27, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005332620.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15862278, 12203999, 18340403, 24480078, 28676128, 8401515) (less)
Likely benign (Jun 19, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227058.5 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	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: 6 Sex: mixed
Uncertain significance (Aug 30, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Mucopolysaccharidosis type I Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000916078.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (2) PubMed: 12203999‚ 8401515 Comment: The IDUA c.245A>C (p.His82Pro) missense variant has been reported in two studies and is found in two individuals in a compound heterozygous state (Clarke and … (more) The IDUA c.245A>C (p.His82Pro) missense variant has been reported in two studies and is found in two individuals in a compound heterozygous state (Clarke and Scott 1993; Venturi et al. 2002). These individuals exhibited an intermediate phenotype characteristic of the Hurler-Scheie syndrome form of mucopolysaccharidosis, type I (MPS I), and also carried a known pathogenic stop-gained variant. The p.His82Pro variant was also reported in a heterozygous state in two additional patients with MPS I in whom a second variant was not identified. The variant was not found in 168 tested control chromosomes. The p.His82Pro variant is reported at a frequency of 0.000017 in the European (non-Finnish) population of the Genome Aggregation Database, though this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, p.His82Pro is classified as a variant is of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hurler syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136674.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Mar 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003817577.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jun 10, 2020)	no assertion criteria provided Method: clinical testing	Mucopolysaccharidosis type I Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002083090.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 82 of the IDUA protein (p.His82Pro). This variant is present in population databases (rs794727239, gnomAD 0.002%). This missense change has been observed in individual(s) with MPS I (PMID: 8401515). ClinVar contains an entry for this variant (Variation ID: 195039). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15862278, 12203999, 18340403, 24480078, 28676128, 8401515)

Comment:

The IDUA c.245A>C (p.His82Pro) missense variant has been reported in two studies and is found in two individuals in a compound heterozygous state (Clarke and Scott 1993; Venturi et al. 2002). These individuals exhibited an intermediate phenotype characteristic of the Hurler-Scheie syndrome form of mucopolysaccharidosis, type I (MPS I), and also carried a known pathogenic stop-gained variant. The p.His82Pro variant was also reported in a heterozygous state in two additional patients with MPS I in whom a second variant was not identified. The variant was not found in 168 tested control chromosomes. The p.His82Pro variant is reported at a frequency of 0.000017 in the European (non-Finnish) population of the Genome Aggregation Database, though this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, p.His82Pro is classified as a variant is of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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 analysis of 30 mucopolysaccharidosis type I patients: evaluation of the mutational spectrum in Italian population and identification of 13 novel mutations.	Venturi N	Human mutation	2002	PMID: 12203999
Two novel mutations causing mucopolysaccharidosis type I detected by single strand conformational analysis of the alpha-L-iduronidase gene.	Clarke LA	Human molecular genetics	1993	PMID: 8401515
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA	-	-	-	-

Text-mined citations for rs794727239 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000203.5(IDUA):c.245A>C (p.His82Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs794727239 ...