NM_000018.4(ACADVL):c.1406G>A (p.Arg469Gln) AND Very long chain acyl-CoA dehydrogenase deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 1, 2019
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:: RCV000169627.5

Allele description

NM_000018.4(ACADVL):c.1406G>A (p.Arg469Gln)

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.1406G>A (p.Arg469Gln)

HGVS:

NC_000017.11:g.7224041G>A
NG_007975.1:g.9208G>A
NG_008391.2:g.1010C>T
NG_033038.1:g.15504C>T
NM_000018.4:c.1406G>AMANE SELECT
NM_001033859.2:c.1340G>A
NM_001270447.1:c.1475G>A
NM_001270448.1:c.1178G>A
NP_000009.1:p.Arg469Gln
NP_000009.1:p.Arg469Gln
NP_001029031.1:p.Arg447Gln
NP_001257376.1:p.Arg492Gln
NP_001257377.1:p.Arg393Gln
NC_000017.10:g.7127360G>A
NM_000018.3:c.1406G>A
P49748:p.Arg469Gln

Protein change:

R393Q

Links:

UniProtKB: P49748#VAR_000361; dbSNP: rs398123083

NCBI 1000 Genomes Browser:

rs398123083

Molecular consequence:

NM_000018.4:c.1406G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001033859.2:c.1340G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270447.1:c.1475G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270448.1:c.1178G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
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
SCV000221156	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Feb 25, 2015)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 24305961, 9973285, 23798014, 17514507 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001364931	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 (2) [See all records that cite these PMIDs] 9973285, 25741868
SCV001413446	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9973285, 17999356, 25834949, 17374501, 27246109, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000221156

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Feb 25, 2015)

unknown

literature only

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV001364931

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

SCV001413446

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2019)

germline

clinical testing

PubMed (6)
[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	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	literature only

Citations

PubMed

Muscle MRI in patients with long-chain fatty acid oxidation disorders.

Diekman EF, van der Pol WL, Nievelstein RA, Houten SM, Wijburg FA, Visser G.

J Inherit Metab Dis. 2014 May;37(3):405-13. doi: 10.1007/s10545-013-9666-3. Epub 2013 Dec 5.

PubMed [citation]

PMID:: 24305961

Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening.

Waisbren SE, Landau Y, Wilson J, Vockley J.

Dev Disabil Res Rev. 2013;17(3):260-8. doi: 10.1002/ddrr.1119.

PubMed [citation]

PMID:: 23798014
PMCID:: PMC4137760

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000221156.1

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

#	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

From Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364931.2

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

Description

The NM_000018.3:c.1406G>A (NP_000009.1:p.Arg469Gln) [GRCH38: NC_000017.11:g.7224041G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. 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 Invitae, SCV001413446.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine with glutamine at codon 469 of the ACADVL protein (p.Arg469Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in an individual affected with very long chain acyl-CoA dehydrogenase deficiency (PMID: 25834949). ClinVar contains an entry for this variant (Variation ID: 92276). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg469 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9973285, 17999356, 27246109, 17374501). 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

Last Updated: May 1, 2021

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