NM_000018.4(ACADVL):c.830AGA[1] (p.Lys278del) AND Very long chain acyl-CoA dehydrogenase deficiency

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Dec 15, 2023
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:: RCV000271659.17

Allele description [Variation Report for NM_000018.4(ACADVL):c.830AGA[1] (p.Lys278del)]

NM_000018.4(ACADVL):c.830AGA[1] (p.Lys278del)

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.830AGA[1] (p.Lys278del)

HGVS:

NC_000017.11:g.7222254AGA[1]
NG_007975.1:g.7421AGA[1]
NG_008391.2:g.2792TCT[1]
NM_000018.4:c.830AGA[1]MANE SELECT
NM_000018.4:c.833_835del
NM_001033859.3:c.764AGA[1]
NM_001270447.2:c.899AGA[1]
NM_001270448.2:c.602AGA[1]
NP_000009.1:p.Lys278del
NP_001029031.1:p.Lys256del
NP_001257376.1:p.Lys301del
NP_001257377.1:p.Lys202del
NC_000017.10:g.7125573AGA[1]
NC_000017.10:g.7125573_7125575del
NM_000018.2:c.833_835delAGA
NM_000018.3:c.833_835del
NM_000018.3:c.833_835delAGA
NM_000018.4:c.833_835delMANE SELECT
NM_000018.4:c.833_835delAGAMANE SELECT

Protein change:

K202del

Links:

dbSNP: rs769280599

NCBI 1000 Genomes Browser:

rs769280599

Molecular consequence:

NM_000018.4:c.830AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001033859.3:c.764AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270447.2:c.899AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001270448.2:c.602AGA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

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
SCV000773902	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9973285, 19327992, 23430950, 30194637, 28492532
SCV001364904	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] 9973285, 25741868
SCV001455131	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002764852	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Dec 13, 2021)	germline	clinical testing	Citation Link,
SCV004215881	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 11, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004241518	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19327992, 24305961, 32463482, 10407852 Citation Link

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Summary from all submissions

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

Citations

PubMed

Successful weight loss in two adult patients diagnosed with late-onset long-chain Fatty Acid oxidation defect.

Zweers H, Timmer C, Rasmussen E, den Heijer M, de Valk H.

JIMD Rep. 2012;6:127-9. doi: 10.1007/8904_2012_131. Epub 2012 Mar 10.

PubMed [citation]

PMID:: 23430950
PMCID:: PMC3565639

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

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000773902.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant, c.833_835del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Lys278del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769280599, gnomAD 0.01%). This variant has been observed in individual(s) with VLCAD deficiency (PMID: 9973285, 19327992, 23430950, 30194637). ClinVar contains an entry for this variant (Variation ID: 281042). 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 Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine, SCV001364904.2

#	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.833_835delAGA (NP_000009.1:p.Lys278del) [GRCH38: NC_000017.11:g.7222257_7222259delAGA] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. 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 Natera, Inc., SCV001455131.1

#	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 Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764852.1

#	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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004215881.1

#	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, SCV004241518.1

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

Description

Variant summary: ACADVL c.833_835delAGA (p.Lys278del) results in an in-frame deletion that is predicted to remove one amino acid from the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein. The variant allele was found at a frequency of 2e-05 in 251438 control chromosomes. c.833_835delAGA has been reported in the literature as a biallelic genotype in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24305961, 32463482, 19327992, 10407852). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. 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

Last Updated: Apr 20, 2024

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