NM_000018.4(ACADVL):c.890AGA[2] (p.Lys299del) AND Very long chain acyl-CoA dehydrogenase deficiency

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

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 8, 2024
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:: RCV000001694.31

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_000017.10:g.7126003_7126005del
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_000018.4:c.896_898delAGA
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]
NC_000017.10:g.7125997_7125999del
NC_000017.10:g.7126003_7126005del
NM_000018.2:c.896_898del
NM_000018.2:c.896_898delAGA
NM_000018.3:c.896_898del
NM_000018.4:c.896_898delMANE SELECT
NM_000018.4:c.896_898delAGAMANE SELECT
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]

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
SCV000021850	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1996)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000220685	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Sep 10, 2014)	unknown	literature only	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000654974	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10738914, 8554073, 9973285, 16982043, 28492532
SCV001364909	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] 8554073, 25741868
SCV003799675	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Mar 17, 2022)	germline	clinical testing	Citation Link,
SCV004215947	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004222934	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10077518, 8554073, 32710939, 33278787 Citation Link

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency.

Pons R, Cavadini P, Baratta S, Invernizzi F, Lamantea E, Garavaglia B, Taroni F.

Pediatr Neurol. 2000 Feb;22(2):98-105.

PubMed [citation]

PMID:: 10738914

Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency.

Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, Ijlst L, Morris A, Pourfarzam M, Bartlett K, Baumgartner ER, deKlerk JB, Schroeder LD, Corydon TJ, Lund H, Winter V, Bross P, Bolund L, Gregersen N.

Am J Hum Genet. 1999 Feb;64(2):479-94.

PubMed [citation]

PMID:: 9973285
PMCID:: PMC1377757

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000021850.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an infant with VLCAD deficiency (201475), Souri et al. (1996) found deletion of nucleotides 895-897 in the ACADVL gene, resulting in deletion of lys299 (K299X).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000220685.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Invitae, SCV000654974.6

#	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.896_898del, results in the deletion of 1 amino acid(s) of the ACADVL protein (p.Lys299del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761162357, gnomAD 0.008%). This variant has been observed in individual(s) with clinical features of very-long-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 8554073, 10738914; Invitae). This variant is also known as c.895_897del and K258del. ClinVar contains an entry for this variant (Variation ID: 92292). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ACADVL function (PMID: 8554073). This variant disrupts the p.Lys299 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 9973285, 16982043), which suggests that this may be a clinically significant amino acid residue. 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, SCV001364909.2

#	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.896_898delAGA (NP_000009.1:p.Lys299del) [GRCH38: NC_000017.11:g.7222684_7222686delAGA] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8554073. 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799675.3

#	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 individuals identified by newborn screening and in an individual described as having very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Lin 2020, Schiff 2013, Souri 1996). This variant is also reported in ClinVar (Variation ID: 92292). It is found in the general population with an overall allele frequency of 0.002% (7/ 281832 alleles) in the Genome Aggregation Database. 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: Lin Y et al. Newborn screening and genetic characteristics of patients with short- and very long-chain acyl-CoA dehydrogenase deficiencies. Clin Chim Acta. 2020 Nov;510:285-290. PMID: 32710939. 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. PMID: 23480858. 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. PMID: 8554073.

#	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, SCV004215947.2

#	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	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, SCV004222934.1

#	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.896_898delAGA (p.Lys299del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 2.4e-05 in 250448 control chromosomes (gnomAD). c.896_898delAGA (also known as c.895_897del and K258del) has been reported in the literature in multiple individuals affected with features of Very Long Chain Acyl-CoA Dehydrogenase Deficiency (examples: Souri_1996, Mathur_1999, Lin_2020, Wang_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant disrupts normal protein activity (Souri_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8554073, 32710939, 10077518, 33278787). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. 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: Sep 16, 2024

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