NM_000018.4(ACADVL):c.1269+1G>A AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Dec 14, 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:: RCV000671502.16

Allele description [Variation Report for NM_000018.4(ACADVL):c.1269+1G>A]

NM_000018.4(ACADVL):c.1269+1G>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.1269+1G>A

HGVS:

NC_000017.11:g.7223731G>A
NG_007975.1:g.8898G>A
NG_008391.2:g.1320C>T
NG_008391.3:g.1319C>T
NG_033038.1:g.15814C>T
NM_000018.4:c.1269+1G>AMANE SELECT
NM_001033859.3:c.1203+1G>A
NM_001270447.2:c.1338+1G>A
NM_001270448.2:c.1041+1G>A
NC_000017.10:g.7127050G>A
NM_000018.3:c.1269+1G>A

Links:

dbSNP: rs773401248

NCBI 1000 Genomes Browser:

rs773401248

Molecular consequence:

NM_000018.4:c.1269+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001033859.3:c.1203+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270447.2:c.1338+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270448.2:c.1041+1G>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
SCV000796484	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Dec 18, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25834949, 21531094, 21932095 Citation Link,
SCV001376995	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 4, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21932095, 25834949, 16199547, 9973285, 11590124, 28492532
SCV001983477	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 22, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21932095, 30194637, 25834949, 32793418 Citation Link,
SCV002088788	Natera, Inc.	no assertion criteria provided	Pathogenic (Jul 20, 2020)	germline	clinical testing
SCV002769783	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (Dec 14, 2022)	germline	curation	Citation Link,
SCV004212659	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2024)	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	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

Very long-chain acyl CoA dehydrogenase deficiency which was accepted as infanticide.

Eminoglu TF, Tumer L, Okur I, Ezgu FS, Biberoglu G, Hasanoglu A.

Forensic Sci Int. 2011 Jul 15;210(1-3):e1-3. doi: 10.1016/j.forsciint.2011.04.003. Epub 2011 Apr 30.

PubMed [citation]

PMID:: 21531094

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000796484.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001376995.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 555644). This variant is also known as IVS12+1G>A. Disruption of this splice site has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 25834949). This variant is present in population databases (rs773401248, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 12 of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983477.1

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

Description

Variant summary: ACADVL c.1269+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251452 control chromosomes. c.1269+1G>A has been reported in the literature as a homozygous genotype in at-least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency, as an uninformative genotype in at-least one individual and in individuals with a carrier genotype (without a second allele specified) (example, Hoffmann_2012, Diekman_2015, Hesse_2018, Maguolo_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete loss of VLCAD activity and long chain-fatty acid oxidation flux (example, Diekman_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Natera, Inc., SCV002088788.1

#	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, SCV002769783.2

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

Description

The c.1269+1G>A variant in ACADVL, also published as IVS12+1G>A, occurs within the canonical splice donor site (+/- 1,2) of intron 12. It is predicted to cause skipping of biologically-relevant-exon 12/20, resulting in an in-frame deletion (removes amino acids 395-423) that is predicted to escape nonsense mediated decay (PVS1_Moderate). This variant has been described without an additional ACADVL variant in 3 individuals identified by newborn screen, identified in an unknown phase to a variant of uncertain significance in two individuals, and has also been identified occurring in the homozygous state in an individual identified by newborn screen (PM3_Supporting, PMIDs: 32793418, 30194637, 25834949, 21932095, 21531094). The individual who carried the c.1269+1G>A variant in the homozygous state also displayed reduced VLCAD enzyme activity, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMID: 25834949). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM3_Supporting, PP4_Moderate, PM2_Supporting (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

From Baylor Genetics, SCV004212659.2

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

Last Updated: Sep 29, 2024

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