NM_002225.5(IVD):c.286+2T>C AND Isovaleryl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Jan 7, 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:: RCV001376756.10

Allele description [Variation Report for NM_002225.5(IVD):c.286+2T>C]

NM_002225.5(IVD):c.286+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.286+2T>C

HGVS:

NC_000015.10:g.40407992T>C
NG_011986.2:g.7508T>C
NM_001159508.3:c.196+2T>C
NM_001354597.3:c.238+2T>C
NM_001354598.3:c.286+2T>C
NM_001354599.3:c.373+2T>C
NM_001354600.3:c.373+2T>C
NM_001354601.3:c.286+2T>C
NM_002225.3:c.295+2T>C
NM_002225.5:c.286+2T>CMANE SELECT
NC_000015.9:g.40700191T>C
NM_002225.5:c.286+2T>C

Links:

dbSNP: rs748026507

NCBI 1000 Genomes Browser:

rs748026507

Molecular consequence:

NM_001159508.3:c.196+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354597.3:c.238+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354598.3:c.286+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354599.3:c.373+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354600.3:c.373+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354601.3:c.286+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_002225.5:c.286+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
SCV001573920	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 7, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 16602101, 28492532
SCV002094390	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Aug 18, 2017)	germline	clinical testing
SCV002806694	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 11, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198016	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2024)	unknown	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	unknown	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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001573920.4

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

Description

This sequence change affects a donor splice site in intron 3 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 (rs748026507, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with IVD-related conditions. ClinVar contains an entry for this variant (Variation ID: 203788). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 Natera, Inc., SCV002094390.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002806694.1

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

From Baylor Genetics, SCV004198016.2

#	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 29, 2024

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