NM_002225.5(IVD):c.456+2T>C AND Isovaleryl-CoA dehydrogenase deficiency

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

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 21, 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:: RCV000178177.19

Allele description

NM_002225.5(IVD):c.456+2T>C

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.456+2T>C

HGVS:

NC_000015.10:g.40410799T>C
NG_011986.2:g.10315T>C
NM_001159508.3:c.366+2T>C
NM_001354597.3:c.408+2T>C
NM_001354598.3:c.456+2T>C
NM_001354599.3:c.543+2T>C
NM_001354600.3:c.543+2T>C
NM_001354601.3:c.456+2T>C
NM_002225.5:c.456+2T>CMANE SELECT
NC_000015.9:g.40702998T>C
NM_002225.3:c.465+2T>C

Links:

dbSNP: rs398123683

NCBI 1000 Genomes Browser:

rs398123683

Molecular consequence:

NM_001159508.3:c.366+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354597.3:c.408+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354598.3:c.456+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354599.3:c.543+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354600.3:c.543+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354601.3:c.456+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_002225.5:c.456+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000631888	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 16602101, 10677295, 24637313, 28492532
SCV001132418	Counsyl	no assertion criteria provided	Likely pathogenic (Apr 2, 2015)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10677295, 24637313, 15486829
SCV002023192	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002094395	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV004198011	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 21, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity.

Vockley J, Ensenauer R.

Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):95-103. Review.

PubMed [citation]

PMID:: 16602101
PMCID:: PMC2652706

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000631888.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects a donor splice site in intron 4 of the IVD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IVD are known to be pathogenic (PMID: 16602101). This variant is present in population databases (rs398123683, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with isovaleric acidemia (PMID: 10677295, 24637313). ClinVar contains an entry for this variant (Variation ID: 94055). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Counsyl, SCV001132418.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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 Revvity Omics, Revvity, SCV002023192.3

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002094395.1

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

#	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 Baylor Genetics, SCV004198011.2

#	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

Last Updated: Sep 16, 2024

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