NM_000018.4(ACADVL):c.1878G>A (p.Trp626Ter) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Aug 6, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000652044.21

Allele description [Variation Report for NM_000018.4(ACADVL):c.1878G>A (p.Trp626Ter)]

NM_000018.4(ACADVL):c.1878G>A (p.Trp626Ter)

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.1878G>A (p.Trp626Ter)

HGVS:

NC_000017.11:g.7225007G>A
NG_007975.1:g.10174G>A
NG_008391.2:g.44C>T
NG_033038.1:g.14538C>T
NM_000018.4:c.1878G>AMANE SELECT
NM_001033859.3:c.1812G>A
NM_001270447.2:c.1947G>A
NM_001270448.2:c.1650G>A
NP_000009.1:p.Trp626Ter
NP_001029031.1:p.Trp604Ter
NP_001257376.1:p.Trp649Ter
NP_001257377.1:p.Trp550Ter
NP_001257377.1:p.Trp550Ter
NC_000017.10:g.7128326G>A
NM_000018.2:c.1878G>A
NM_000018.3:c.1878G>A
NM_001270448.1:c.1650G>A
p.Trp550*

Protein change:

W550*

Links:

dbSNP: rs1555529186

NCBI 1000 Genomes Browser:

rs1555529186

Molecular consequence:

NM_000018.4:c.1878G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001033859.3:c.1812G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001270447.2:c.1947G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001270448.2:c.1650G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Very long chain acyl-CoA dehydrogenase deficiency (ACADVLD)
Synonyms:: VLCAD deficiency
Identifiers:: MONDO: MONDO:0008723; MedGen: C3887523; Orphanet: 26793; OMIM: 201475

Recent activity

Clear Turn Off Turn On

PREDICTED: putative dual specificity protein phosphatase DSP8 [Prunus mume]
PREDICTED: putative dual specificity protein phosphatase DSP8 [Prunus mume]
gi|645274695|ref|XP_008242462.1|

Protein
AGENCOURT_77835899 NICHD_XGC_skin_m Xenopus laevis cDNA clone IMAGE:8643358 5', ...
AGENCOURT_77835899 NICHD_XGC_skin_m Xenopus laevis cDNA clone IMAGE:8643358 5', mRNA sequence
gi|95012052|gnl|dbEST|39154069|gb|E 36.1|

Nucleotide
AGENCOURT_74297086 NICHD_XGC_limb_m Xenopus laevis cDNA clone IMAGE:8533423 5', ...
AGENCOURT_74297086 NICHD_XGC_limb_m Xenopus laevis cDNA clone IMAGE:8533423 5', mRNA sequence
gi|92062716|gnl|dbEST|37992739|gb|E 92.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000773910	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31031081, 26385305, 32778825, 28492532
SCV000883338	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Aug 9, 2019)	germline	clinical testing	Citation Link,
SCV001364944	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] 26385305, 25741868
SCV005053250	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 26, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005381305	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 6, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26385305, 32778825 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	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

Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency.

Rovelli V, Manzoni F, Viau K, Pasquali M, Longo N.

Mol Genet Metab. 2019 May;127(1):64-73. doi: 10.1016/j.ymgme.2019.04.001. Epub 2019 Apr 16.

PubMed [citation]

PMID:: 31031081

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000773910.5

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Val642Met) have been determined to be pathogenic (PMID: 31031081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 541724). This premature translational stop signal has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305, 32778825). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp626*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the ACADVL protein.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883338.2

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

Description

The ACADVL c.1878G>A; p.Trp626Ter variant is reported in the medical literature in at least one individual sent for newborn screening of very-long-chain acyl-CoA dehydrogenase deficiency (Miller 2015). This variant is reported in ClinVar (Variation ID: 541724), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a premature termination codon and truncates the terminal 30 amino acids. These amino acids are unique amongst acyl-CoA dehydrogenases, but have no reported critical function (Goetzman 2007, McAndrew 2008). Due to limited information, the clinical significance of the p.Trp626Ter variant is uncertain at this time. References: Goetzman ES et al. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol Genet Metab. 2007 Jun;91(2):138-47. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45.

#	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, SCV001364944.2

#	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.1878G>A (NP_000009.1:p.Trp626Ter) [GRCH38: NC_000017.11:g.7225007G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 26385305. 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 Baylor Genetics, SCV005053250.1

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005381305.1

#	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.1878G>A (p.Trp626X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 30 amino acids of the protein. The variant was absent in 251306 control chromosomes (gnomAD). c.1878G>A has been reported in the literature in individuals undergoing newborn screening (e.g., Miller_2015, Adhikari_2020), however, the phenotype or if a second ACADVL variant was detected in trans in these individuals was not reported. These reports therefore do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 26385305). ClinVar contains an entry for this variant (Variation ID: 541724). Additionally, downstream variants have been reported in association with Very long chain acyl-CoA dehydrogenase deficiency in HGMD and have been classified as pathogenic/likely pathogenic by our laboratory and others in ClinVar. 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

Last Updated: Oct 26, 2024

ClinVar

Relating variation to medicine