NM_014049.5(ACAD9):c.1298G>A (p.Arg433Gln) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 19, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001753708.5

Allele description [Variation Report for NM_014049.5(ACAD9):c.1298G>A (p.Arg433Gln)]

NM_014049.5(ACAD9):c.1298G>A (p.Arg433Gln)

Gene:

ACAD9:acyl-CoA dehydrogenase family member 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q21.3

Genomic location:

Preferred name:

NM_014049.5(ACAD9):c.1298G>A (p.Arg433Gln)

HGVS:

NC_000003.12:g.128908204G>A
NG_017064.1:g.33715G>A
NM_014049.5:c.1298G>AMANE SELECT
NP_054768.2:p.Arg433Gln
NC_000003.11:g.128627047G>A
NM_014049.4:c.1298G>A
NR_033426.2:n.1546G>A

Protein change:

R433Q

Links:

dbSNP: rs781156571

NCBI 1000 Genomes Browser:

rs781156571

Molecular consequence:

NM_014049.5:c.1298G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_033426.2:n.1546G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001985819	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 27, 2021)	germline	clinical testing	Citation Link,
SCV003525354	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 19, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25721401, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001985819

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 27, 2021)

germline

clinical testing

Citation Link,

SCV003525354

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 19, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency.

Schiff M, Haberberger B, Xia C, Mohsen AW, Goetzman ES, Wang Y, Uppala R, Zhang Y, Karunanidhi A, Prabhu D, Alharbi H, Prochownik EV, Haack T, Häberle J, Munnich A, Rötig A, Taylor RW, Nicholls RD, Kim JJ, Prokisch H, Vockley J.

Hum Mol Genet. 2015 Jun 1;24(11):3238-47. doi: 10.1093/hmg/ddv074. Epub 2015 Feb 26.

PubMed [citation]

PMID:: 25721401
PMCID:: PMC4424958

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

Details of each submission

From GeneDx, SCV001985819.2

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

Description

Functional analysis of R433Q found it is associated with significantly reduced ACAD9 activity compared to wild-type (Schiff et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25721401, 30025539, 26669660, 28284481)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003525354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 433 of the ACAD9 protein (p.Arg433Gln). This variant is present in population databases (rs781156571, gnomAD 0.0009%). This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 25721401). ClinVar contains an entry for this variant (Variation ID: 242462). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACAD9 protein function. Experimental studies have shown that this missense change affects ACAD9 function (PMID: 25721401). 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

Last Updated: Sep 29, 2024

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