NM_000018.4(ACADVL):c.890AGA[2] (p.Lys299del) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 9, 2018
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:: RCV000077926.6

Allele description

NM_000018.4(ACADVL):c.890AGA[2] (p.Lys299del)

Gene:

ACADVL:acyl-CoA dehydrogenase very long chain [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000018.4(ACADVL):c.890AGA[2] (p.Lys299del)

HGVS:

NC_000017.11:g.7222678AGA[2]
NG_007975.1:g.7845AGA[2]
NG_008391.2:g.2365TCT[2]
NM_000018.4:c.890AGA[2]MANE SELECT
NM_001033859.3:c.824AGA[2]
NM_001270447.2:c.959AGA[2]
NM_001270448.2:c.662AGA[2]
NP_000009.1:p.Lys299del
NP_000009.1:p.Lys299del
NP_001029031.1:p.Lys277del
NP_001257376.1:p.Lys322del
NP_001257377.1:p.Lys223del
NC_000017.10:g.7125997AGA[2]
NM_000018.2:c.896_898delAGA
NM_000018.3:c.896_898del
NM_001270448.1:c.668_670delAGA
p.Lys223del

Protein change:

K223del

Links:

OMIM: 609575.0007; dbSNP: rs387906252

NCBI 1000 Genomes Browser:

rs387906252

Molecular consequence:

NM_000018.4:c.890AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001033859.3:c.824AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270447.2:c.959AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270448.2:c.662AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000224740	EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (May 15, 2013)	germline	clinical testing	Citation Link,
SCV000321373	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 26, 2017)	germline	clinical testing	Citation Link,
SCV000883335	ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Apr 9, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000224740

EGL Genetic Diagnostics, Eurofins Clinical Diagnostics

criteria provided, single submitter

(EGL Classification Definitions)

Pathogenic
(May 15, 2013)

germline

clinical testing

Citation Link,

SCV000321373

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Apr 26, 2017)

germline

clinical testing

Citation Link,

SCV000883335

ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Apr 9, 2018)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000224740.5

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

From GeneDx, SCV000321373.6

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

Description

The c.896_898delAGA variant in the ACADVL gene has been reported previously in association with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Souri et al., 1996). The deletion causes the loss of a single Lysine residue at amino acid position 299, denoted p.Lys299del. Analysis of the c.896_898delAGA variant in CHO cells found that the resultant mRNA and protein were unstable, that the resultant protein appeared abnormal in dimer assembly and was associated with undetectable activity of the VLCAD enzyme (Souri et al., 1996). The c.896_898delAGA 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. In summary, we interpret c.896_898delAGA to be a pathogenic variant.

#	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 ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000883335.1

#	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.896_898delAGA; p.Lys299del variant (rs398123094) has been described in an individual identified by newborn screening and in an individual described as having very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Schiff 2013, Souri 1996). This variant is reported in ClinVar (Variation ID: 92292), and is found in the general population with an overall allele frequency of 0.02% (3/12518 alleles) in the Exome Variant Server. This variant deletes a single lysine residue leaving the rest of the protein in-frame. The lysine at codon 299 is conserved across mammals and the loss of this codon has been shown to result in an unstable transcript (Souri 1996). Based on available information, this variant is considered to be pathogenic. REFERENCES Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7. Souri M et al. Mutation analysis of very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. Am J Hum Genet. 1996 Jan;58(1):97-106.

#	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: Sep 19, 2021

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