NM_000018.4(ACADVL):c.541dup (p.His181fs) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 8, 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:: RCV001200674.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.541dup (p.His181fs)]

NM_000018.4(ACADVL):c.541dup (p.His181fs)

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.541dup (p.His181fs)

Other names:

NM_000018.4(ACADVL):c.541dup; p.His181fs

HGVS:

NC_000017.11:g.7221601dup
NG_007975.1:g.6768dup
NG_008391.2:g.3452dup
NM_000018.4:c.541dupMANE SELECT
NM_001033859.3:c.475dup
NM_001270447.2:c.610dup
NM_001270448.2:c.313dup
NP_000009.1:p.His181fs
NP_001029031.1:p.His159fs
NP_001257376.1:p.His204fs
NP_001257377.1:p.His105fs
NC_000017.10:g.7124920dup
NM_000018.3:c.541dupC

Protein change:

H105fs

Links:

dbSNP: rs1337636757

NCBI 1000 Genomes Browser:

rs1337636757

Molecular consequence:

NM_000018.4:c.541dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001033859.3:c.475dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270447.2:c.610dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270448.2:c.313dup - 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

Recent activity

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Nucleotide
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daj36c06.x1 NICHD_XGC_OO1 Xenopus laevis cDNA clone IMAGE:5078410 3' similar to ...
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gi|17404594|gnl|dbEST|10490870|gb|B 23.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001364960	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]
SCV002538668	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Mar 8, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001364960

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]

SCV002538668

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(clingen acadvl acmg specifications v1)

Pathogenic
(Mar 8, 2022)

germline

curation

Citation Link

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

Citations

PubMed

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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364960.2

#	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.541dupC (NP_000009.1:p.His181ProfsTer72) [GRCH38: NC_000017.11:g.7221601dup] 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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002538668.2

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

Description

The c.541dup (p.His181fs)variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 9/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one patient with this variant displayed enzyme activity levels measured in lymphocytes of 6% of control values, which is highly specific for VLCAD deficiency (PP4_moderate, PMID 32463482). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as 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, PP4_moderate, PM2_supporting. VCEP specifications version2; 10/15/21.

#	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: Apr 15, 2023

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