VCV000195038.24 - ClinVar

NM_000203.5(IDUA):c.235G>A (p.Ala79Thr)

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.

(13)

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.

Benign/Likely benign; other

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000203.5(IDUA):c.235G>A (p.Ala79Thr)

Variation ID: 195038 Accession: VCV000195038.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.3 4: 987885 (GRCh38) [ NCBI UCSC ] 4: 981673 (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	Mar 8, 2017	Sep 29, 2024	Nov 1, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000203.5:c.235G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000194.2:p.Ala79Thr	missense
NM_022042.4:c.*948C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_134425.4:c.576+3243C>T		intron variant
NM_213613.4:c.*948C>T		3 prime UTR
NR_110313.1:n.323G>A		non-coding transcript variant
NC_000004.12:g.987885G>A
NC_000004.11:g.981673G>A
NG_008103.1:g.5889G>A
NG_033042.1:g.10552C>T
LRG_1277:g.5889G>A
LRG_1277t1:c.235G>A	LRG_1277p1:p.Ala79Thr

... more HGVS ... less HGVS

Protein change

A79T

Other names

Canonical SPDI

NC_000004.12:987884:G:A

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.

0.01018 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00239

Exome Aggregation Consortium (ExAC) 0.00362

The Genome Aggregation Database (gnomAD) 0.00910

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00964

Trans-Omics for Precision Medicine (TOPMed) 0.00964

1000 Genomes Project 0.01018

1000 Genomes Project 30x 0.01218

Links

ClinGen: CA201508 dbSNP: rs58037052 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 provided	Benign/Likely benign; other (6)	criteria provided, multiple submitters, no conflicts	Sep 18, 2018	RCV000422439.17
Mucopolysaccharidosis type 1	Benign; other (3)	criteria provided, multiple submitters, no conflicts	Dec 26, 2018	RCV000708549.11
Hurler syndrome	Likely benign (1)	criteria provided, single submitter	May 16, 2018	RCV000674553.2
not specified	Benign (2)	criteria provided, single submitter	Nov 1, 2021	RCV001194419.5
Calcium oxalate urolithiasis	Likely benign (1)	criteria provided, single submitter	Jul 19, 2021	RCV002500480.2

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.
Benign (Jan 27, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511059.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
other (May 25, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227056.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	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: 16 Sex: mixed
Likely benign (May 16, 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: SCV000799908.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 27238910‚ 27939258
other pseudodeficiency allele (Dec 26, 2018)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000837659.2 First in ClinVar: Oct 10, 2018 Last updated: Aug 14, 2019	Publications: PubMed (1) PubMed: 28492532
Benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Mucopolysaccharidosis type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001317785.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Benign (Sep 18, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001784074.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Comment: This variant is associated with the following publications: (PMID: 27939258)
Benign (Nov 01, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001363959.2 First in ClinVar: Jun 22, 2020 Last updated: Dec 25, 2021	Publications: PubMed (3) PubMed: 27939258‚ 27238910‚ 32432561 Comment: Variant summary: IDUA c.235G>A (p.Ala79Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: IDUA c.235G>A (p.Ala79Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 270526 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.235G>A, also has been reported in the literature as a well-known pseudodeficiency allele, prevalent in the African American subpopulation. Individuals with pseudodeficiency allele(s) exhibit decreased alpha-L-iduronidase enzyme activity in biochemical assays using artificial substrates, but otherwise show no evidence of disease (see e.g. in Clarke_2016). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign pseudodeficiency allele (n=6) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign. (less)
Likely benign (Jul 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrolithiasis susceptibility caused by SLC26A1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811181.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005263615.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Uncertain significance (Jul 27, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000801292.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800421.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921769.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (-)	no classification provided Method: literature only	Mucopolysaccharidosis type 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002016347.2 First in ClinVar: Nov 20, 2021 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1162 BookShelf: NBK1162 Comment: Pseudodeficiency variants
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

Variant summary: IDUA c.235G>A (p.Ala79Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 270526 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.235G>A, also has been reported in the literature as a well-known pseudodeficiency allele, prevalent in the African American subpopulation. Individuals with pseudodeficiency allele(s) exhibit decreased alpha-L-iduronidase enzyme activity in biochemical assays using artificial substrates, but otherwise show no evidence of disease (see e.g. in Clarke_2016). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign pseudodeficiency allele (n=6) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.

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
Mucopolysaccharidosis Type I.	Adam MP	-	2024	PMID: 20301341
The combined use of enzyme activity and metabolite assays as a strategy for newborn screening of mucopolysaccharidosis type I.	Polo G	Clinical chemistry and laboratory medicine	2020	PMID: 32432561
Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management.	Clarke LA	The Journal of pediatrics	2017	PMID: 27939258
Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry.	Elliott S	Molecular genetics and metabolism	2016	PMID: 27238910
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA	-	-	-	-

Text-mined citations for rs58037052 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000203.5(IDUA):c.235G>A (p.Ala79Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs58037052 ...