NM_000018.4:c.1367G>A

Variant names:

• chr17-7224002-G-A
• rs794727112
• NM_000018.4:c.1367G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1367G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 456 (p.Arg456His). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 30194637, 17206456). Of those individuals, one individual was presumed homozygous for the variant and two were confirmed compound heterozygous for the variant and a distinct variant, one of which is approved by the ACADVL VCEP as pathogenic (PM3, 1.5 points, PMIDs: 30194637, 17206456). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001709 in the European non-Finnish 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 0.947, 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: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA240224/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:2
• Conservation: PhyloP100: 8.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.1367G>A	p.Arg456His	missense_variant	Exon 14 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1367G>A	p.Arg456His	missense_variant	Exon 14 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5 Uncertain:1

Apr 23, 2024

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1367G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of arginine by histidine at amino acid 456 (p.Arg456His). This variant has been detected in at least four individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMIDs: 30194637, 17206456). Of those individuals, one individual was presumed homozygous for the variant and two were confirmed compound heterozygous for the variant and a distinct variant, one of which is approved by the ACADVL VCEP as pathogenic (PM3, 1.5 points, PMIDs: 30194637, 17206456). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001709 in the European non-Finnish 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 0.947, 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: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). -

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 456 of the ACADVL protein (p.Arg456His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 17206456, 30194637). ClinVar contains an entry for this variant (Variation ID: 194316). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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.1367G>A (NP_000009.1:p.Arg456His) [GRCH38: NC_000017.11:g.7224002G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285; 17206456. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 -

Dec 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000018.3(ACADVL):c.1367G>A(R456H) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. R456H has been observed in cases with relevant disease (PMID: 26182500, 29268767, 9973285, Schymik_2007_(no PMID; dissertation), 17206456). Functional assessments of this variant are not available in the literature. R456H has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1367G>A(R456H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not provided Uncertain:1

Nov 24, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.95
MutPred		0.95		.;Loss of MoRF binding (P = 0.0371);.;
MVP		1.0
MPC		0.73
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.99
gMVP		0.96

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

Other links and lift over

dbSNP: rs794727112; hg19: chr17-7127321; COSMIC: COSV50039309; COSMIC: COSV50039309;