NM_000018.4(ACADVL):c.997_998insT (p.Ala333fs) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 28, 2023
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:: RCV003164887.2

Allele description [Variation Report for NM_000018.4(ACADVL):c.997_998insT (p.Ala333fs)]

NM_000018.4(ACADVL):c.997_998insT (p.Ala333fs)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.997_998insT (p.Ala333fs)

Other names:

NM_001270448.2:c.769_770insT

HGVS:

NC_000017.11:g.7222785_7222786insT
NG_007975.1:g.7952_7953insT
NG_008391.2:g.2265_2266insA
NG_008391.3:g.2264_2265insA
NM_000018.4:c.997_998insTMANE SELECT
NM_001033859.3:c.931_932insT
NM_001270447.2:c.1066_1067insT
NM_001270448.2:c.769_770insT
NP_000009.1:p.Ala333fs
NP_001029031.1:p.Ala311fs
NP_001257376.1:p.Ala356fs
NP_001257377.1:p.Ala257fs
NC_000017.10:g.7126104_7126105insT

Protein change:

A257fs

Molecular consequence:

NM_000018.4:c.997_998insT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001033859.3:c.931_932insT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270447.2:c.1066_1067insT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001270448.2:c.769_770insT - 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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gi|1484317|gnl|dbEST|634552|gb|AA02 1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003853589	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Mar 28, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003853589

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(clingen acadvl acmg specifications v1)

Pathogenic
(Mar 28, 2023)

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	curation

Details of each submission

From ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV003853589.1

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

Description

The c.997_998insT (p.Ala333ValfsTer26) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 10/20 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 ꞵ-Oxidation Flux <20% of normal, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PMID:17999356). 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 VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PP4_moderate, PM2_supporting (ACADVL VCEP specifications version 1; approved November 8, 2021)

#	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: Jun 23, 2024

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