NM_000018.4(ACADVL):c.1593dup (p.Ser532fs) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Sep 5, 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:: RCV000477936.6

Allele description [Variation Report for NM_000018.4(ACADVL):c.1593dup (p.Ser532fs)]

NM_000018.4(ACADVL):c.1593dup (p.Ser532fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.1593dup (p.Ser532fs)

Other names:

NM_000018.4(ACADVL):c.1593dup; p.Ser532fs

HGVS:

NC_000017.11:g.7224381dup
NG_007975.1:g.9548dup
NG_008391.2:g.671dup
NG_033038.1:g.15165dup
NM_000018.4:c.1593dupMANE SELECT
NM_001033859.3:c.1527dup
NM_001270447.2:c.1662dup
NM_001270448.2:c.1365dup
NP_000009.1:p.Ser532fs
NP_001029031.1:p.Ser510fs
NP_001257376.1:p.Ser555fs
NP_001257377.1:p.Ser456fs
NC_000017.10:g.7127700dup
NM_000018.3:c.1593dupG

Protein change:

S456fs

Links:

dbSNP: rs1060499596

NCBI 1000 Genomes Browser:

rs1060499596

Molecular consequence:

NM_000018.4:c.1593dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001033859.3:c.1527dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270447.2:c.1662dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270448.2:c.1365dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000536845	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (May 9, 2015)	germline	research
SCV001364936	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] 26385305, 25741868
SCV002769760	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (Sep 5, 2022)	germline	curation	Citation Link,
SCV004211842	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 28, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	research
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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536845.1

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

#	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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364936.2

#	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.1593dupG (NP_000009.1:p.Ser532GlufsTer30) [GRCH38: NC_000017.11:g.7224381dupG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 26385305. 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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002769760.2

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

Description

The c.1593dup (p.Ser532GlufsTer30) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 09-05-2022).

#	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, SCV004211842.1

#	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: Dec 30, 2023

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