17-7224179-G-C

Variant names:

• chr17-7224179-G-C
• rs759775666
• NM_000018.4:c.1468G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2_Supporting PM3_Supporting PM1 PP4_Moderate PP3 PP1

This summary comes from the ClinGen Evidence Repository: The c.1468G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 490 (p.Ala490Pro), also known as Ala450Pro when numbered from the mature protein. This variant has been detected in at least 5 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 2 were compound heterozygous for the variant and distinct pathogenic or likely pathogenic variant, presumed to be in trans (PM3_Supporting, PMID:26453363, 30194637). This variant has been described in at least 3 unrelated individuals who displayed VLCAD enzyme activity <20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:26453363, 14517516, 30194637). The variant has been reported to segregate with VLCAD deficiency in 2 affected siblings from 1 family (PP1, PMID:14517516). This variant resides within a region, amino acids 481-516, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PMID:18227065, 20060901). A substrate specificity assay showed this variant displays abnormal substrate specificity; however, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel (PMID:9839948). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.794, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel:  PM1, PM2_Supporting, PM3_Supporting, PP1, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8338123/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 4.20
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• very long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1468G>C	p.Ala490Pro	missense_variant	Exon 15 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1468G>C	p.Ala490Pro	missense_variant	Exon 15 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251362 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:6

Apr 13, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 490 of the ACADVL protein (p.Ala490Pro). This variant is present in population databases (rs759775666, gnomAD 0.004%). This missense change has been observed in individual(s) with known or suggested very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 10077518, 14517516, 26453363). This variant is also known as A450P. ClinVar contains an entry for this variant (Variation ID: 474888). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACADVL protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 17374501). For these reasons, this variant has been classified as Pathogenic. -

Apr 11, 2023

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1468G>C (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by proline at amino acid 490 (p.Ala490Pro), also known as Ala450Pro when numbered from the mature protein. This variant has been detected in at least 5 individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Of those individuals, 2 were compound heterozygous for the variant and distinct pathogenic or likely pathogenic variant, presumed to be in trans (PM3_Supporting, PMID: 26453363, 30194637). This variant has been described in at least 3 unrelated individuals who displayed VLCAD enzyme activity <20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID:26453363, 14517516, 30194637). The variant has been reported to segregate with VLCAD deficiency in 2 affected siblings from 1 family (PP1, PMID: 14517516). This variant resides within a region, amino acids 481-516, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PMID: 18227065, 20060901). A substrate specificity assay showed this variant displays abnormal substrate specificity; however, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9839948). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.794, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_Supporting, PM3_Supporting, PP1, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). -

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.1468G>C (NP_000009.1:p.Ala490Pro) [GRCH38: NC_000017.11:g.7224179G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9839948; 10077518. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Mar 20, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACADVL-related disorder Pathogenic:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADVL c.1468G>C variant is predicted to result in the amino acid substitution p.Ala490Pro. This variant was reported in multiple patients with clinical and biochemical features consistent with Very long chain acyl-CoA dehydrogenase deficiency (Diekman et al. 2015. PubMed ID: 26453363, Spiekerkoetter et al. 2003. PubMed ID: 14517516, Mathur et al. 1999. PubMed ID: 10077518, Goetzman et al. 2007. PubMed ID: 17374501). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD, and is interpreted as likely pathogenic by the ClinGen ACADVL Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/474888/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Uncertain	0.71	.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	2.9	.;M;.
PhyloP100		4.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	D;.;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.015	D;.;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.98, 0.99	.;D;D
Vest4		0.49
MVP		0.99
MPC		0.73
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs759775666; hg19: chr17-7127498;