ClinVar Genomic variation as it relates to human health
NM_002225.5(IVD):c.149G>A (p.Arg50His)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002225.5(IVD):c.149G>A (p.Arg50His)
Variation ID: 370843 Accession: VCV000370843.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 40407640 (GRCh38) [ NCBI UCSC ] 15: 40699841 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 6, 2017 Jul 15, 2024 Feb 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002225.5:c.149G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002216.3:p.Arg50His missense NM_001159508.3:c.145-299G>A intron variant NM_001354597.3:c.101G>A NP_001341526.1:p.Arg34His missense NM_001354598.3:c.149G>A NP_001341527.2:p.Arg50His missense NM_001354599.3:c.149G>A NP_001341528.2:p.Arg50His missense NM_001354600.3:c.149G>A NP_001341529.2:p.Arg50His missense NM_001354601.3:c.149G>A NP_001341530.2:p.Arg50His missense NR_148925.2:n.561G>A non-coding transcript variant NC_000015.10:g.40407640G>A NC_000015.9:g.40699841G>A NG_011986.2:g.7156G>A - Protein change
- R50H, R34H
- Other names
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- Canonical SPDI
- NC_000015.10:40407639:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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IVD | - | - |
GRCh38 GRCh37 |
746 | 756 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 22, 2024 | RCV000411182.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 9, 2022 | RCV001848730.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 27, 2021 | RCV002523859.2 |
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
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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
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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
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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. |
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Likely pathogenic
(Apr 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000486257.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440727.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
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Pathogenic
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002104326.2
First in ClinVar: Mar 19, 2022 Last updated: Mar 04, 2023 |
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; Sometimes reported as R21H or R50H using alternate nomenclature; This variant is associated with the following publications: (PMID: 25220015, 19099814, 15486829, 22960500, 33565069, 32778825, 32505769, 31442447, 27904153, 17027310, 31707166) (less)
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000931264.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 53 of the IVD protein (p.Arg53His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 53 of the IVD protein (p.Arg53His). This variant is present in population databases (rs2229311, gnomAD 0.006%). This missense change has been observed in individual(s) with isovaleric acidemia (PMID: 15486829, 17027310, 19099814, 27904153). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.149G>A (p.Arg21His). ClinVar contains an entry for this variant (Variation ID: 370843). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in individuals with IVD-related conditions (PMID: 10677295, 15486829, 17576084), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003560072.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.158G>A (p.R53H) alteration is located in exon 2 (coding exon 2) of the IVD gene. This alteration results from a G to A substitution … (more)
The c.158G>A (p.R53H) alteration is located in exon 2 (coding exon 2) of the IVD gene. This alteration results from a G to A substitution at nucleotide position 158, causing the arginine (R) at amino acid position 53 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (7/251478) total alleles studied. The highest observed frequency was 0.01% (2/34592) of Latino alleles. This alteration, also described as p.R21H in literature, has been reported in the homozygous state or compound heterozygous state with a second IVD alteration in several patients with isovaleric acidemia (Ensenauer, 2004; Lin, 2007; Couce, 2017; Li, 2019; Ibarra-González, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(Feb 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004198018.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Isovaleryl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005073896.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
The missense c.149G>A (p.Arg50His) variant in the IVD gene has been observed in several patients with isovaleric acidemia (Ensenauer, Regina et al., 2004). The variant … (more)
The missense c.149G>A (p.Arg50His) variant in the IVD gene has been observed in several patients with isovaleric acidemia (Ensenauer, Regina et al., 2004). The variant is present in a mutational hotspot. A different amino acid change p.Arg50Cys has been reported as pathogenic (van der Weerd K, et al., 2017). This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 50 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg50His in IVD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Molecular analysis using targeted next generation DNA sequencing and clinical spectrum of Mexican patients with isovaleric acidemia. | Ibarra-González I | Clinica chimica acta; international journal of clinical chemistry | 2020 | PMID: 31707166 |
Eight novel mutations detected from eight Chinese patients with isovaleric acidemia. | Li Y | Clinica chimica acta; international journal of clinical chemistry | 2019 | PMID: 31442447 |
Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia. | Couce ML | Journal of human genetics | 2017 | PMID: 27904153 |
Phenotypic and genotypic spectrum of Turkish patients with isovaleric acidemia. | Ozgul RK | European journal of medical genetics | 2014 | PMID: 25220015 |
[Clinical and mutational study of a Chinese infant with isovaleric acidemia]. | Qiu WJ | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2008 | PMID: 19099814 |
Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with isovaleric acidemia. | Lee YW | Molecular genetics and metabolism | 2007 | PMID: 17576084 |
Genetic mutation profile of isovaleric acidemia patients in Taiwan. | Lin WD | Molecular genetics and metabolism | 2007 | PMID: 17027310 |
A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. | Ensenauer R | American journal of human genetics | 2004 | PMID: 15486829 |
Exon skipping in IVD RNA processing in isovaleric acidemia caused by point mutations in the coding region of the IVD gene. | Vockley J | American journal of human genetics | 2000 | PMID: 10677295 |
Text-mined citations for rs2229311 ...
HelpRecord last updated Jul 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.