ClinVar Genomic variation as it relates to human health
NM_002225.5(IVD):c.149G>C (p.Arg50Pro)
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>C (p.Arg50Pro)
Variation ID: 188922 Accession: VCV000188922.40
- 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 Mar 29, 2015 Oct 8, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002225.5:c.149G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002216.3:p.Arg50Pro missense NM_001159508.3:c.145-299G>C intron variant NM_001354597.3:c.101G>C NP_001341526.1:p.Arg34Pro missense NM_001354598.3:c.149G>C NP_001341527.2:p.Arg50Pro missense NM_001354599.3:c.149G>C NP_001341528.2:p.Arg50Pro missense NM_001354600.3:c.149G>C NP_001341529.2:p.Arg50Pro missense NM_001354601.3:c.149G>C NP_001341530.2:p.Arg50Pro missense NR_148925.2:n.561G>C non-coding transcript variant NC_000015.10:g.40407640G>C NC_000015.9:g.40699841G>C NG_011986.2:g.7156G>C - Protein change
- R50P, R34P
- Other names
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- Canonical SPDI
- NC_000015.10:40407639:G:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
Help
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 |
753 | 763 |
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
Help
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 (6) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2024 | RCV000169289.13 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 3, 2020 | RCV001090731.24 | |
IVD-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jan 31, 2024 | RCV003927565.3 |
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
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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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Pathogenic
(Sep 13, 2020)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001578737.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
This sequence change replaces arginine with proline at codon 53 of the IVD protein (p.Arg53Pro). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with proline at codon 53 of the IVD protein (p.Arg53Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs2229311, ExAC 0.02%). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 27904153, 26018748, 9665741). This variant is also known as p.Arg21Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 188922). This variant has been reported to affect IVD protein function (PMID: 9665741). This variant disrupts the p.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 110677295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 25, 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: SCV001163380.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
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Likely pathogenic
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: no
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251800.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Pathogenic
(Sep 27, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100218.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: IVD c.149G>C (p.Arg50Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: IVD c.149G>C (p.Arg50Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251478 control chromosomes (gnomAD). c.149G>C has been reported in the literature in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (examples: Mohsen_1998, Ensenauer_2004, and Couce_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Mohsen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 27904153, 15486829, 9665741). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 01, 2018)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246420.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 19, 2014)
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criteria provided, single submitter
Method: literature only
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Isovaleryl-CoA dehydrogenase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220605.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Sep 29, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893369.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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Isovaleryl-coa dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002094382.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Jan 31, 2024)
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no assertion criteria provided
Method: clinical testing
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IVD-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004740574.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The IVD c.158G>C variant is predicted to result in the amino acid substitution p.Arg53Pro. This variant, alternately described in the literature as Arg21Pro or c.149G>C, … (more)
The IVD c.158G>C variant is predicted to result in the amino acid substitution p.Arg53Pro. This variant, alternately described in the literature as Arg21Pro or c.149G>C, p.Arg50Pro, has been recurrently reported in patients with isovaleric acidemia and has been reported to impact protein function (Mohsen et al. 1998. PubMed ID: 9665741; Ensenauer et al. 2004. PubMed ID: 15486829; Sakamoto et al. 2015. PubMed ID: 26018748; Couce et al. 2016. PubMed ID: 27904153; D'Annibale et al. 2021. PubMed ID: 34535384; Mütze et al. 2021. PubMed ID: 33496032). Different substitutions of the same amino acid (p.Arg53Cys, p.Arg53His, p.Arg53Leu) have also been reported in isovaleric acidemia patients (Ensenauer et al. 2004. PubMed ID: 15486829; Lee et al. 2007. PubMed ID: 17576084; Li et al. 2019. PubMed ID: 31442447). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted 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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Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia. | Couce ML | Journal of human genetics | 2017 | PMID: 27904153 |
Phenotypic Variability and Newly Identified Mutations of the IVD Gene in Japanese Patients with Isovaleric Acidemia. | Sakamoto O | The Tohoku journal of experimental medicine | 2015 | PMID: 26018748 |
An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers. | Smith PJ | Human molecular genetics | 2006 | PMID: 16825284 |
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 |
Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia. | Mohsen AW | Biochemistry | 1998 | PMID: 9665741 |
- | - | - | - | PMID: 110677295 |
Text-mined citations for rs2229311 ...
HelpRecord last updated Oct 08, 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.