NM_000018.4(ACADVL):c.1375C>T (p.Arg459Trp) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 21, 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:: RCV000652041.10

Allele description [Variation Report for NM_000018.4(ACADVL):c.1375C>T (p.Arg459Trp)]

NM_000018.4(ACADVL):c.1375C>T (p.Arg459Trp)

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.1375C>T (p.Arg459Trp)

HGVS:

NC_000017.11:g.7224010C>T
NG_007975.1:g.9177C>T
NG_008391.2:g.1041G>A
NG_033038.1:g.15535G>A
NM_000018.4:c.1375C>TMANE SELECT
NM_001033859.3:c.1309C>T
NM_001270447.2:c.1444C>T
NM_001270448.2:c.1147C>T
NP_000009.1:p.Arg459Trp
NP_001029031.1:p.Arg437Trp
NP_001257376.1:p.Arg482Trp
NP_001257377.1:p.Arg383Trp
NP_001257377.1:p.Arg383Trp
NC_000017.10:g.7127329C>T
NM_000018.3:c.1375C>T
NM_001270448.1:c.1147C>T
P49748:p.Arg459Trp

Protein change:

R383W

Links:

UniProtKB: P49748#VAR_000359; dbSNP: rs766742117

NCBI 1000 Genomes Browser:

rs766742117

Molecular consequence:

NM_000018.4:c.1375C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.3:c.1309C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.2:c.1444C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.2:c.1147C>T - 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
SCV000773905	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 14, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9973285, 10738914, 21932095, 26385305, 14517516, 19327992, 21429517, 23798014, 28492532
SCV001364926	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9973285, 21932095, 25741868
SCV004213666	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 21, 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

SCV000773905

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 14, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001364926

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 1, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004213666

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 21, 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

Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency.

Pons R, Cavadini P, Baratta S, Invernizzi F, Lamantea E, Garavaglia B, Taroni F.

Pediatr Neurol. 2000 Feb;22(2):98-105.

PubMed [citation]

PMID:: 10738914

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ.

Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

PubMed [citation]

PMID:: 26385305
PMCID:: PMC4790081

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000773905.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 459 of the ACADVL protein (p.Arg459Trp). This variant is present in population databases (rs766742117, gnomAD 0.009%). This missense change has been observed in individual(s) with biochemical features of very long chain acyl-CoA dehydrogenase deficiency but in whom no second allele was reported (PMID: 9973285, 10738914, 21932095, 26385305; Invitae). ClinVar contains an entry for this variant (Variation ID: 203584). 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. This variant disrupts the p.Arg459 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14517516, 19327992, 21429517, 23798014). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364926.2

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

Description

The NM_000018.3:c.1375C>T (NP_000009.1:p.Arg459Trp) [GRCH38: NC_000017.11:g.7224010C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 21932095. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

#	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, SCV004213666.2

#	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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