NM_000018.4(ACADVL):c.1678+4A>T AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 6, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000412992.3

Allele description [Variation Report for NM_000018.4(ACADVL):c.1678+4A>T]

NM_000018.4(ACADVL):c.1678+4A>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.1678+4A>T

HGVS:

NC_000017.11:g.7224556A>T
NG_007975.1:g.9723A>T
NG_008391.2:g.495T>A
NG_033038.1:g.14989T>A
NM_000018.4:c.1678+4A>TMANE SELECT
NM_001033859.3:c.1612+4A>T
NM_001270447.2:c.1747+4A>T
NM_001270448.2:c.1450+4A>T
NC_000017.10:g.7127875A>T
NM_000018.2:c.1678+4A>T
NM_000018.3:c.1678+4A>T

Links:

dbSNP: rs1057518417

NCBI 1000 Genomes Browser:

rs1057518417

Molecular consequence:

NM_000018.4:c.1678+4A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001033859.3:c.1612+4A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001270447.2:c.1747+4A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001270448.2:c.1450+4A>T - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000492027	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Nov 18, 2016)	germline	clinical testing	Citation Link,
SCV002015185	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 6, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26385305, 30194637 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000492027

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Nov 18, 2016)

germline

clinical testing

Citation Link,

SCV002015185

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 6, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States.

Miller MJ, Burrage LC, Gibson JB, Strenk ME, Lose EJ, Bick DP, Elsea SH, Sutton VR, Sun Q, Graham BH, Craigen WJ, Zhang VW, Wong LJ.

Mol Genet Metab. 2015 Nov;116(3):139-45. doi: 10.1016/j.ymgme.2015.08.011. Epub 2015 Sep 2.

PubMed [citation]

PMID:: 26385305
PMCID:: PMC4790081

The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD).

Hesse J, Braun C, Behringer S, Matysiak U, Spiekerkoetter U, Tucci S.

J Inherit Metab Dis. 2018 Nov;41(6):1169-1178. doi: 10.1007/s10545-018-0245-5. Epub 2018 Sep 7.

PubMed [citation]

PMID:: 30194637

Details of each submission

From GeneDx, SCV000492027.1

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

Description

The c.1678+4A>T variant in the ACADVL gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant reduces the quality of the splice donor site in intron 17, and is expected to cause abnormal gene splicing. The c.1678+4A>T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1678+4A>T as a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	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, SCV002015185.1

#	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.1678+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, while two predict the variant weakens a 5' 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 247870 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1678+4A>T has been reported in the literature in individual(s) affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Miller_2015, Hesse_2018), where one of the reported individuals was noted to carry a potentially pathogenic ACADVL variant on the other allele, and 15% residual enzyme activity measured from patient derived lymphocytes (Hesse_2018). These reports do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. Three 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Oct 20, 2024

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