NM_000018.4(ACADVL):c.1077+2T>C AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Sep 29, 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:: RCV000411047.20

Allele description [Variation Report for NM_000018.4(ACADVL):c.1077+2T>C]

NM_000018.4(ACADVL):c.1077+2T>C

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.1077+2T>C

HGVS:

NC_000017.11:g.7222867T>C
NG_007975.1:g.8034T>C
NG_008391.2:g.2184A>G
NG_008391.3:g.2183A>G
NM_000018.4:c.1077+2T>CMANE SELECT
NM_001033859.3:c.1011+2T>C
NM_001270447.2:c.1146+2T>C
NM_001270448.2:c.849+2T>C
NC_000017.10:g.7126186T>C
NM_000018.3:c.1077+2T>C

Links:

dbSNP: rs1057516370

NCBI 1000 Genomes Browser:

rs1057516370

Molecular consequence:

NM_000018.4:c.1077+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001033859.3:c.1011+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270447.2:c.1146+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270448.2:c.849+2T>C - 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
SCV001338229	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 29, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9973285, 25338548 Citation Link,
SCV001364913	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 (3) [See all records that cite these PMIDs] 9973285, 25338548, 25741868
SCV001402471	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 11590124, 9973285, 25338548, 30194637, 28492532
SCV002060291	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Pathogenic (Nov 17, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9973285, 25338548 Citation Link,
SCV002088777	Natera, Inc.	no assertion criteria provided	Pathogenic (Oct 6, 2021)	germline	clinical testing
SCV002576779	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Pathogenic (Sep 29, 2022)	germline	curation	Citation Link,
SCV004212693	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 25, 2023)	unknown	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse.

Cox KB, Hamm DA, Millington DS, Matern D, Vockley J, Rinaldo P, Pinkert CA, Rhead WJ, Lindsey JR, Wood PA.

Hum Mol Genet. 2001 Sep 15;10(19):2069-77.

PubMed [citation]

PMID:: 11590124

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338229.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: ACADVL c.1077+2T>C 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: Three predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249894 control chromosomes. c.1077+2T>C has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency with a characteristic acyl-carnitine profile (example, Andersen_1999, Scalais_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Scalais_2015). This relatively high VLCAD activity in lymphocytes was attributed to oral riboflavin supplementation at the time of analysis. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely 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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364913.2

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

Description

The NM_000018.3:c.1077+2T>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222867T>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 25338548. 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001402471.5

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

Description

This sequence change affects a donor splice site in intron 10 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 9973285, 25338548, 30194637). ClinVar contains an entry for this variant (Variation ID: 370279). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been 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 Myriad Genetics, Inc., SCV002060291.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

NM_000018.3(ACADVL):c.1077+2T>C is a canonical splice variant classified as pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. c.1077+2T>C has been observed in cases with relevant disease (PMID: 9973285, 25338548). Functional assessments of this variant are available in the literature (PMID: 25338548). c.1077+2T>C has not been observed in population frequency databases. In summary, NM_000018.3(ACADVL):c.1077+2T>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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 Natera, Inc., SCV002088777.1

#	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, SCV002576779.2

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

Description

The NM_000018.4:c.1077+2T>C variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/20, 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). This variant has been detected in three homozygous siblings with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who inherited the variant from heterozygous parents (PMID:25338548)(PM3_Supporting, points=0.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two patients with this variant displayed elevated C14:1 levels ≥ 1.0 μM and VLCAD enzyme activity <20% of control in proband fibroblast (PMID:25338548, 9973285), which is highly specific for VLCADD (PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM2_supporting,PM3_Supporting, PP4_Moderate.

#	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, SCV004212693.1

#	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: Oct 20, 2024

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