NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Dec 15, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000174654.20

Allele description [Variation Report for NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter)]

NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter)

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.1357C>T (p.Arg453Ter)

Other names:

NM_000018.4(ACADVL):c.1357C>T; p.Arg453Ter

HGVS:

NC_000017.11:g.7223992C>T
NG_007975.1:g.9159C>T
NG_008391.2:g.1059G>A
NG_033038.1:g.15553G>A
NM_000018.4:c.1357C>TMANE SELECT
NM_001033859.3:c.1291C>T
NM_001270447.2:c.1426C>T
NM_001270448.2:c.1129C>T
NP_000009.1:p.Arg453Ter
NP_001029031.1:p.Arg431Ter
NP_001257376.1:p.Arg476Ter
NP_001257377.1:p.Arg377Ter
NC_000017.10:g.7127311C>T
NM_000018.3:c.1357C>T

Protein change:

R377*

Links:

dbSNP: rs794727113

NCBI 1000 Genomes Browser:

rs794727113

Molecular consequence:

NM_000018.4:c.1357C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001033859.3:c.1291C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001270447.2:c.1426C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001270448.2:c.1129C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000486650	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jul 12, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26385305, 17999356 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000823991	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 14, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9973285, 11590124, 17999356, 28492532
SCV001364979	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 (1) [See all records that cite this PMID]
SCV002088789	Natera, Inc.	no assertion criteria provided	Pathogenic (Dec 31, 2020)	germline	clinical testing
SCV002769778	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Dec 15, 2022)	germline	curation	Citation Link,
SCV003808494	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004214184	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 17, 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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.

Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N.

Am J Hum Genet. 1999 Feb;64(2):479-94.

PubMed [citation]

PMID:: 9973285
PMCID:: PMC1377757

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000486650.2

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

#	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 Invitae, SCV000823991.6

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

Description

This sequence change creates a premature translational stop signal (p.Arg453*) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (rs794727113, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 17999356). ClinVar contains an entry for this variant (Variation ID: 194317). 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, SCV001364979.2

#	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.1357C>T (NP_000009.1:p.Arg453Ter) [GRCH38: NC_000017.11:g.7223992C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, 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 Natera, Inc., SCV002088789.1

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

#	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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002769778.2

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

Description

The NM_000018.4(ACADVL):c.1357C>T (p.Arg453Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 14/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). This variant was detected and confirmed in-trans with the pathogenic c.1349G>A (p.R450H) in a patient with VLCAD-deficiency (PM3, PMID:33150772). This variant was also reported in one patient with a positive newborn screen for VLCAD-deficiency (PMID:26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting (PM2_Supporting). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM3,PM2_Supporting.

#	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, SCV003808494.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004214184.1

#	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: Mar 16, 2024

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