NM_000018.4(ACADVL):c.1838G>A (p.Arg613Gln) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 27, 2023
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:: RCV001060887.19

Allele description [Variation Report for NM_000018.4(ACADVL):c.1838G>A (p.Arg613Gln)]

NM_000018.4(ACADVL):c.1838G>A (p.Arg613Gln)

Gene:

ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1838G>A (p.Arg613Gln)

HGVS:

NC_000017.11:g.7224967G>A
NG_007975.1:g.10134G>A
NG_008391.2:g.84C>T
NG_033038.1:g.14578C>T
NM_000018.4:c.1838G>AMANE SELECT
NM_001033859.3:c.1772G>A
NM_001270447.2:c.1907G>A
NM_001270448.2:c.1610G>A
NP_000009.1:p.Arg613Gln
NP_001029031.1:p.Arg591Gln
NP_001257376.1:p.Arg636Gln
NP_001257377.1:p.Arg537Gln
NP_001257377.1:p.Arg537Gln
NC_000017.10:g.7128286G>A
NM_000018.3:c.1838G>A
NM_000018.4:c.1838G>A
NM_001270448.1:c.1610G>A

Protein change:

R537Q

Links:

dbSNP: rs534647044

NCBI 1000 Genomes Browser:

rs534647044

Molecular consequence:

NM_000018.4:c.1838G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1907G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.1610G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
Synonyms:: VLCAD deficiency
Identifiers:: MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001225604	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 30194637, 32710939, 17999356, 18670371, 23430950, 26881790, 28755359, 28492532 Citation Link,
SCV002021275	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 25, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002074384	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26385305, 30194637, 33610471, 32710939 Citation Link,
SCV004215103	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 14, 2023)	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

Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy.

Gobin-Limballe S, Djouadi F, Aubey F, Olpin S, Andresen BS, Yamaguchi S, Mandel H, Fukao T, Ruiter JP, Wanders RJ, McAndrew R, Kim JJ, Bastin J.

Am J Hum Genet. 2007 Dec;81(6):1133-43. Epub 2007 Oct 29.

PubMed [citation]

PMID:: 17999356
PMCID:: PMC2276345

Development of a new enzymatic diagnosis method for very-long-chain Acyl-CoA dehydrogenase deficiency by detecting 2-hexadecenoyl-CoA production and its application in tandem mass spectrometry-based selective screening and newborn screening in Japan.

Tajima G, Sakura N, Shirao K, Okada S, Tsumura M, Nishimura Y, Ono H, Hasegawa Y, Hata I, Naito E, Yamaguchi S, Shigematsu Y, Kobayashi M.

Pediatr Res. 2008 Dec;64(6):667-72. doi: 10.1203/PDR.0b013e318187cc44.

PubMed [citation]

PMID:: 18670371

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225604.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 613 of the ACADVL protein (p.Arg613Gln). This variant is present in population databases (rs534647044, gnomAD 0.008%). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 30194637, 32710939; https://www.mdpi.com/2409-515X/3/1/2/htm). ClinVar contains an entry for this variant (Variation ID: 618502). 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 ACADVL protein function with a positive predictive value of 95%. This variant disrupts the p.Arg613 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17999356, 18670371, 23430950, 26881790, 28755359). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001365134.2

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

Description

The NM_000018.3:c.1838G>A (NP_000009.1:p.Arg613Gln) [GRCH38: NC_000017.11:g.7224967G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BP4

#	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 Revvity Omics, Revvity, SCV002021275.3

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074384.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: ACADVL c.1838G>A (p.Arg613Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251108 control chromosomes. c.1838G>A has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Olpin_2017, Miller_2015, Hesse_2018, Lin_2020, Guffon_2021, Olsson_2021). These data indicate that the variant is likely to be associated with disease. Enzyme activity of compound heterozygous patients cells were measured at <20% of wild-type (Olpin_2017, Olsson_2021). Additionally, a different variant affecting the same amino acid has been reported in association with VLCAD (R613W). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as likely pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was 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, SCV004215103.2

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001365134	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Nov 1, 2019)	germline	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

SCV001365134

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 1, 2019)

germline

clinical testing

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

Last Updated: Sep 29, 2024

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