NM_000018.4(ACADVL):c.1605+2T>A AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (3 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:: RCV001200786.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.1605+2T>A]

NM_000018.4(ACADVL):c.1605+2T>A

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.1605+2T>A

HGVS:

NC_000017.11:g.7224395T>A
NG_007975.1:g.9562T>A
NG_008391.2:g.656A>T
NG_008391.3:g.655A>T
NG_033038.1:g.15150A>T
NM_000018.4:c.1605+2T>AMANE SELECT
NM_001033859.3:c.1539+2T>A
NM_001270447.2:c.1674+2T>A
NM_001270448.2:c.1377+2T>A
NC_000017.10:g.7127714T>A
NM_000018.3:c.1605+2T>A

Links:

dbSNP: rs1597537351

NCBI 1000 Genomes Browser:

rs1597537351

Molecular consequence:

NM_000018.4:c.1605+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001033859.3:c.1539+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270447.2:c.1674+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270448.2:c.1377+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001364984	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]
SCV003936871	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,
SCV004812273	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001364984

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]

SCV003936871

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,

SCV004812273

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 1, 2024)

germline

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

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, SCV001364984.2

#	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.1605+2T>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7224395T>A] 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, SCV003936871.1

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

Description

The c.1605+2T>A (p.?) variant in ACADVL occurs within the canonical splice donor site (+2) of intron 16. It is predicted to cause skipping of biologically-relevant-exon 16/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). To our knowledge, this variant has not been reported in the literature in any individuals with VLCADD. To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD 2.1.1 (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 Molecular Genetics, Royal Melbourne Hospital, SCV004812273.1

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

Description

This sequence change in ACADVL occurs within the canonical splice donor site of intron 16. It is predicted to cause skipping of biologically relevant exon 16/20, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant is absent from the population database gnomAD v4.0. To our knowledge, this variant has not been previously reported in the relevant scientific literature. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1, 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

Last Updated: Apr 15, 2024

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