NM_002225.5(IVD):c.149G>A (p.Arg50His) AND Isovaleryl-CoA dehydrogenase deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Feb 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000411182.12

Allele description

NM_002225.5(IVD):c.149G>A (p.Arg50His)

Gene:

IVD:isovaleryl-CoA dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_002225.5(IVD):c.149G>A (p.Arg50His)

HGVS:

NC_000015.10:g.40407640G>A
NG_011986.2:g.7156G>A
NM_001159508.3:c.145-299G>A
NM_001354597.3:c.101G>A
NM_001354598.3:c.149G>A
NM_001354599.3:c.149G>A
NM_001354600.3:c.149G>A
NM_001354601.3:c.149G>A
NM_002225.5:c.149G>AMANE SELECT
NP_001341526.1:p.Arg34His
NP_001341527.2:p.Arg50His
NP_001341528.2:p.Arg50His
NP_001341529.2:p.Arg50His
NP_001341530.2:p.Arg50His
NP_002216.3:p.Arg50His
NC_000015.9:g.40699841G>A
NM_002225.3:c.158G>A
NR_148925.2:n.561G>A

Protein change:

R34H

Links:

dbSNP: rs2229311

NCBI 1000 Genomes Browser:

rs2229311

Molecular consequence:

NM_001159508.3:c.145-299G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354597.3:c.101G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354598.3:c.149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354599.3:c.149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354600.3:c.149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354601.3:c.149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002225.5:c.149G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148925.2:n.561G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Isovaleryl-CoA dehydrogenase deficiency (IVA)
Synonyms:: Isovaleric acid CoA dehydrogenase deficiency; Isovaleric acidemia; Isovaleryl CoA carboxylase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009475; MedGen: C0268575; Orphanet: 33; OMIM: 243500

Recent activity

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Homo sapiens glutamate ionotropic receptor kainate type subunit 1 (GRIK1), trans...
Homo sapiens glutamate ionotropic receptor kainate type subunit 1 (GRIK1), transcript variant 1, mRNA
gi|1002341788|ref|NM_000830.4|

Nucleotide
SRX5066987 (1)
SRA

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000486257	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Apr 28, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25220015, 17027310, 15486829, 19099814 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000931264	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17027310, 19099814, 27904153, 10677295, 15486829, 17576084, 28492532
SCV001440727	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198018	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 22, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005073896	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenotypic and genotypic spectrum of Turkish patients with isovaleric acidemia.

Ozgul RK, Karaca M, Kilic M, Kucuk O, Yucel-Yilmaz D, Unal O, Hismi B, Aliefendioglu D, Sivri S, Tokatli A, Coskun T, Dursun A.

Eur J Med Genet. 2014 Oct;57(10):596-601. doi: 10.1016/j.ejmg.2014.08.006. Epub 2014 Sep 8.

PubMed [citation]

PMID:: 25220015

Genetic mutation profile of isovaleric acidemia patients in Taiwan.

Lin WD, Wang CH, Lee CC, Lai CC, Tsai Y, Tsai FJ.

Mol Genet Metab. 2007 Feb;90(2):134-9. Epub 2006 Oct 4.

PubMed [citation]

PMID:: 17027310

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000486257.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000931264.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440727.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004198018.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005073896.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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