NM_000018.4(ACADVL):c.1077+1G>T AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Likely pathogenic (7 submissions)
Last evaluated:: Sep 22, 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:: RCV000412397.20

Allele description [Variation Report for NM_000018.4(ACADVL):c.1077+1G>T]

NM_000018.4(ACADVL):c.1077+1G>T

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+1G>T

HGVS:

NC_000017.11:g.7222866G>T
NG_007975.1:g.8033G>T
NG_008391.2:g.2185C>A
NG_008391.3:g.2184C>A
NM_000018.4:c.1077+1G>TMANE SELECT
NM_001033859.3:c.1011+1G>T
NM_001270447.2:c.1146+1G>T
NM_001270448.2:c.849+1G>T
NC_000017.10:g.7126185G>T
NM_000018.2:c.1077+1G>T
NM_000018.3:c.1077+1G>T

Links:

dbSNP: rs140989450

NCBI 1000 Genomes Browser:

rs140989450

Molecular consequence:

NM_000018.4:c.1077+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001033859.3:c.1011+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270447.2:c.1146+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001270448.2:c.849+1G>T - 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
SCV000916404	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 6, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21932095, 29961767 Citation Link,
SCV000954513	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 6, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16199547, 9973285, 11590124, 21932095, 25338548, 30194637, 28492532
SCV001364911	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 (2) [See all records that cite these PMIDs] 21932095, 25741868
SCV002060305	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 19, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002576739	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (clingen acadvl acmg specifications v1)	Likely pathogenic (Sep 22, 2022)	germline	curation	Citation Link,
SCV003829875	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004215169	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 20, 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

Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy.

Minoche AE, Horvat C, Johnson R, Gayevskiy V, Morton SU, Drew AP, Woo K, Statham AL, Lundie B, Bagnall RD, Ingles J, Semsarian C, Seidman JG, Seidman CE, Dinger ME, Cowley MJ, Fatkin D.

Genet Med. 2019 Mar;21(3):650-662. doi: 10.1038/s41436-018-0084-7. Epub 2018 Jul 2.

PubMed [citation]

PMID:: 29961767
PMCID:: PMC7271716

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 (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916404.3

#	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+1G>T 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 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 249894 control chromosomes. c.1077+1G>T has been reported in the literature in at least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency with residual enzyme activity of 36%. A second mutation was not identifed in this patient (Hoffmann_2012). The variant has also been reported in a patient with familial dilated cardiomyopathy, however co-occurrence with a pathogenic mutation in TTN (c.49458G>A, p.W16486X) was reported in this individual (Minoche_2019). These data do not allow any conclusion about variant significance. Four other 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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 Invitae, SCV000954513.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

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. 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 present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 25338548, 30194637). ClinVar contains an entry for this variant (Variation ID: 370482).

#	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, SCV001364911.2

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

Description

The NM_000018.3:c.1077+1G>T (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222866G>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 21932095. 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 Myriad Genetics, Inc., SCV002060305.2

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

Description

NM_000018.3(ACADVL):c.1077+1G>T is a canonical splice variant classified as likely pathogenic in the context of very-long-chain acyl-CoA dehydrogenase deficiency. c.1077+1G>T has been observed in cases with relevant disease (PMID: 21932095). Functional assessments of this variant are not available in the literature. c.1077+1G>T has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_000018.3(ACADVL):c.1077+1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. 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 ClinGen ACADVL Variant Curation Expert Panel, ClinGen, SCV002576739.2

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

Description

The c.1077+1G>T variant in ACADVL is a splice site variant affecting the canonical donor splice site in intron 10. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present at low frequency (1 allele, <0.1%) in large population database (PM2_supporting, gnomad). This variant has been reported in abnormal newborn screen with 36% residual enzyme activity (PP4 not met) without clinical confirmation or a second variant identified (PMID 21932095). In summary, this variant meets criteria to be classified as likely pathogenic for VLCAD in an AR manner. ACADVL-specific ACMG/AMP criteria applied: 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

From Revvity Omics, Revvity, SCV003829875.2

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

From Baylor Genetics, SCV004215169.1

#	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: Mar 16, 2024

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