NM_002225.5(IVD):c.1066G>A (p.Asp356Asn) AND Isovaleryl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 5, 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:: RCV000557255.13

Allele description [Variation Report for NM_002225.5(IVD):c.1066G>A (p.Asp356Asn)]

NM_002225.5(IVD):c.1066G>A (p.Asp356Asn)

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.1066G>A (p.Asp356Asn)

Other names:

p.D359N:GAC>AAC; p.Asp356Asn

HGVS:

NC_000015.10:g.40416290G>A
NG_011986.2:g.15806G>A
NM_001159508.3:c.976G>A
NM_001354597.3:c.1018G>A
NM_001354598.3:c.1066G>A
NM_001354599.3:c.1153G>A
NM_001354600.3:c.1153G>A
NM_001354601.3:c.1066G>A
NM_002225.5:c.1066G>AMANE SELECT
NP_001152980.2:p.Asp326Asn
NP_001341526.1:p.Asp340Asn
NP_001341527.2:p.Asp356Asn
NP_001341528.2:p.Asp385Asn
NP_001341529.2:p.Asp385Asn
NP_001341530.2:p.Asp356Asn
NP_002216.3:p.Asp356Asn
NC_000015.9:g.40708489G>A
NM_002225.3:c.1075G>A
NP_002216.2:p.Asp359Asn
NR_148925.2:n.1478G>A

Protein change:

D326N

Links:

dbSNP: rs398123679

NCBI 1000 Genomes Browser:

rs398123679

Molecular consequence:

NM_001159508.3:c.976G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354597.3:c.1018G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354598.3:c.1066G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354599.3:c.1153G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354600.3:c.1153G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354601.3:c.1066G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002225.5:c.1066G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148925.2:n.1478G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000631881	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198044	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 5, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000631881

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004198044

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 5, 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	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000631881.8

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 359 of the IVD protein (p.Asp359Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of isovaleric acidemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 94050). 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. 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 Baylor Genetics, SCV004198044.2

#	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: Oct 13, 2024

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