NM_002225.5(IVD):c.490A>G (p.Met164Val) AND Isovaleryl-CoA dehydrogenase deficiency

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jul 19, 2022
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:: RCV001060370.9

Allele description [Variation Report for NM_002225.5(IVD):c.490A>G (p.Met164Val)]

NM_002225.5(IVD):c.490A>G (p.Met164Val)

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.490A>G (p.Met164Val)

HGVS:

NC_000015.10:g.40411293A>G
NG_011986.2:g.10809A>G
NM_001159508.3:c.400A>G
NM_001354597.3:c.442A>G
NM_001354598.3:c.490A>G
NM_001354599.3:c.577A>G
NM_001354600.3:c.577A>G
NM_001354601.3:c.490A>G
NM_002225.5:c.490A>GMANE SELECT
NP_001152980.2:p.Met134Val
NP_001341526.1:p.Met148Val
NP_001341527.2:p.Met164Val
NP_001341528.2:p.Met193Val
NP_001341529.2:p.Met193Val
NP_001341530.2:p.Met164Val
NP_002216.3:p.Met164Val
NC_000015.9:g.40703492A>G
NC_000015.9:g.40703492A>G
NM_002225.3:c.499A>G
NR_148925.2:n.902A>G

Protein change:

M134V

Links:

dbSNP: rs574434706

NCBI 1000 Genomes Browser:

rs574434706

Molecular consequence:

NM_001159508.3:c.400A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354597.3:c.442A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354598.3:c.490A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354599.3:c.577A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354600.3:c.577A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354601.3:c.490A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002225.5:c.490A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148925.2:n.902A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV001225053	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 19, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 32505769, 26018748, 27904153, 31707166, 28492532
SCV001278445	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV001456708	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jun 23, 2018)	germline	clinical testing
SCV002318750	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26018748, 32505769, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia.

Couce ML, Aldamiz-Echevarría L, Bueno MA, Barros P, Belanger-Quintana A, Blasco J, García-Silva MT, Márquez-Armenteros AM, Vitoria I, Vives I, Navarrete R, Fernández-Marmiesse A, Pérez B, Pérez-Cerdá C.

J Hum Genet. 2017 Mar;62(3):355-360. doi: 10.1038/jhg.2016.144. Epub 2016 Dec 1.

PubMed [citation]

PMID:: 27904153

Molecular analysis using targeted next generation DNA sequencing and clinical spectrum of Mexican patients with isovaleric acidemia.

Ibarra-González I, Fernández-Lainez C, Guillén-López S, López-Mejía L, Belmont-Matínez L, Sokolsky TD, Amin VR, Kitchener RL, Vela-Amieva M, Naylor EW, Bhattacharjee A.

Clin Chim Acta. 2020 Feb;501:216-221. doi: 10.1016/j.cca.2019.10.041. Epub 2019 Nov 9.

PubMed [citation]

PMID:: 31707166

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225053.2

#	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 replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 167 of the IVD protein (p.Met167Val). This variant is present in population databases (rs574434706, gnomAD 0.1%). This missense change has been observed in individual(s) with a positive newborn screening result for IVD-related disease (PMID: 32505769). ClinVar contains an entry for this variant (Variation ID: 855170). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Met167 amino acid residue in IVD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26018748, 27904153, 31707166). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Illumina Laboratory Services, Illumina, SCV001278445.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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., SCV001456708.1

#	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 3billion, SCV002318750.1

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

Description

Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:26018748). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.929>=0.6, 3CNET: 0.938>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001427). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Sep 29, 2024

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