dbSNP rs769280599: ACADVL:p.Lys278del (chr17-7222253-GAGA-G) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_000018.4(ACADVL):c.833_835delAGA(p.Lys278del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,613,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:12U:1

Conservation

PhyloP100: 7.81

Variant links:

Genes affected

ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a modified_residue N6-acetyllysine; alternate (size 0) in uniprot entity ACADV_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000018.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 17-7222253-GAGA-G is Pathogenic according to our data. Variant chr17-7222253-GAGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281042.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4 link	c.833_835delAGA	p.Lys278del	disruptive_inframe_deletion	Exon 9 of 20	ENST00000356839.10	NP_000009.1	P49748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 link	c.833_835delAGA	p.Lys278del	disruptive_inframe_deletion	Exon 9 of 20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251438

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1460906

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

726760

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Pathogenic:8

Dec 15, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 13, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 16, 2024

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000018.4 c.833_835del (p.Lys278del) variant in ACADVL is an in-frame deletion (removes amino acids Lys278) in exon 9/20 that is not predicted to impact splicing (SpliceAI: 0.01). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The c.833_835del variant is predicted to cause a change in the length of the protein (p.Lys278del) due to an in-frame deletion of an amino acid in a non-repeat region (PM4). This variant is reported in the literature in multiple individuals affected with very long-chain acyl-CoA dehydrogenase deficiency in both compound heterozygous and homozygous fashion, with at least one of whom displayed elevated C14:1 carnitine level (1.3 µmol/L) and reduced VLCAD enzyme levels (17% WT control), which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 19327992). This patient also carried a pathogenic variant c.1376G>A in trans (PM3 score = 1.0, PM3, PMID: 19327992). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM4, PP4_Moderate, PM3 (ACADVL VCEP specifications version 1; approved November 9, 2021). -

Feb 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2Uncertain:1

Apr 07, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACADVL: PM3:Very Strong, PM2, PP4:Moderate, PM4:Supporting -

Jan 27, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; This variant is associated with the following publications: (PMID: 19327992, 32463482, 30194637, 23430950, 9973285, 24305961) -

ACADVL-related disorder

Pathogenic:1

May 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADVL c.833_835delAGA variant is predicted to result in an in-frame deletion (p.Lys278del). This variant has been reported in multiple individuals with Very long chain acyl-CoA dehydrogenase deficiency (see for example, Andresen et al 1999. PubMed ID: 9973285; Laforêt et al. 2009. PubMed ID: 19327992). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7125572-GAGA-G). This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Oct 14, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.833_835delAGA (p.K278del) alteration, located in coding exon 9 of the ACADVL gene, results from an in-frame deletion of 3 nucleotides at positions 833 to 835. This results in the deletion of a lysine residue at codon 278. Based on data from gnomAD, the c.833_835delAGA allele has an overall frequency of <0.01% (5/251438) total alleles studied. The highest observed frequency was 0.01% (2/16252) of African alleles. This mutation was identified in several individuals with very long-chain acyl-CoA dehydrogenase deficiency, in the both the homozygous and compound heterozygous state, with reduced enzyme activity compared to wild type (Laforêt, 2009; Zweers, 2012; Diekman, 2014; Diekman, 2016; Hesse, 2018; Knottnerus, 2020). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over