rs112406105

chr17-7223152-G-Achr17-7223152-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000018.4(ACADVL):c.1097G>A(p.Arg366His) variant causes a missense change. The variant allele was found at a frequency of 0.0000564 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 6.94

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7223151-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 17-7223152-G-A is Pathogenic according to our data. Variant chr17-7223152-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203580.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-7223152-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1097G>A	p.Arg366His	missense_variant	11/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1097G>A	p.Arg366His	missense_variant	11/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251484 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461550 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 09, 2019	The ACADVL c.1097G>A (p.Arg366His) missense variant has been reported in at least four studies in which it is identified in at least seven individuals with VLCAD deficiency including in a homozygous state in one individual, in a compound heterozygous state in three individuals, in cis with another missense variant, both of which are in trans with a third missense variant in one individual, and in a heterozygous state in two individuals in whom it is unclear if they carry a second variant (Andresen et al. 1999; Boneh et al. 2006; Antunes et al. 2013; Evans et al. 2016). The p.Arg366His variant was absent from 100 control alleles and is reported at a frequency of 0.000098 in the South Asian population of the Genome Aggregation Database. Biochemical studies confirmed the VLCAD deficiency in all patients. Western blot analysis revealed reduced or barely detectable protein levels in fibroblasts from a patient carrying the p.Arg366His variant (Andresen et al. 1999). Several studies note that the variant is associated with a milder phenotype (Gobin-Limballe et al. 2010; Antunes et al. 2013; Brown et al. 2014). Structural analysis of the VLCAD protein suggests that the p.Arg366His variant would induce major structural alterations in substrate-binding, FAD-binding and in enzyme monomer-monomer interactions (Gobin-Limballe et al. 2010). The Arg366 site is thought to be a potential hotspot for variants (Andresen et al. 1999). Based on the collective evidence, the p.Arg366His variant is classified as pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 22, 2022	The c.1097G>A (p.Arg366His) variant in ACADVL has been reported in the literature in patients with VLCADD or increased C14:1 acylcarnitine levels (PP4; PMID: 9973285, 20060901, 27246109, 24263034, 32558070). The variant has been detected as homozygote (PMID:24263034), or compound heterozygote with truncating/pathogenic variants, however without phase confirmation (PMID: 32558070, 27246109, 20060901, PM3). The highest population minor allele frequency in gnomAD is 0.0001 in the South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant resides within a region defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285, 20060901, PM1). The computational predictor REVEL gives a score of 0.98, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PP4, PM1, PM3, PM2_Supporting, PP3). -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.1097G>A (NP_000009.1:p.Arg366His) [GRCH38: NC_000017.11:g.7223152G>A] 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: PS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been observed as homozygous or compound heterozygous change in several individuals affected with very long chain acyl-CoA dehydrogenase (VLCAD)(PMID: 9973285, 20060901, 24263034, 27246109). This variant is also known as p.Arg326His in the literature. ClinVar contains an entry for this variant (Variation ID: 203580). A different amino acid change at the same residue (p.Arg366Cys) have been reported in association with VLCAD deficiency (PMID 8845838, 21932095) supporting the functional importance of this region of the protein. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/282884) and thus is presumed to be rare. The c.1166G>A (p.Arg389His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1166G>A (p.Arg389His) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 25, 2022	The ACADVL c.1097G>A; p.Arg366His variant (rs112406105), also known as Arg326His, has been reported in individuals with VLCAD deficiency both in the homozygous state and as compound heterozygous with another ACADVL pathogenic variant (Andresen 1999, Antunes 2013, Evans 2016, Gobin-Limballe 2010). Additionally, a different alteration at this codon (p.Arg366Cys) has also been associated with VLCAD deficiency and is considered pathogenic (Andresen 1996, Hoffman 2012, Spiekerkoetter 2010). The p.Arg366His variant is listed in ClinVar (Variation ID: 203580) and observed in the general population with low overall allele frequency of 0.003% (8/282,884 alleles) in the Genome Aggregation Database. The arginine at codon 366 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.975). Based on the above information, the p.Arg366His variant is considered pathogenic. References: Andresen BS et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999 Feb;64(2):479-94. PMID: 9973285. Andresen BS et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996 Apr;5(4):461-72. PMID: 8845838. Antunes AP et al. Intermittent rhabdomyolysis with adult onset associated with a mutation in the ACADVL gene. J Clin Neuromuscul Dis. 2013 Dec;15(2):69-72. PMID: 24263034. Evans M et al. VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria. Mol Genet Metab. 2016 Aug;118(4):282-7. PMID: 27246109. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010 May;1802(5):478-84. PMID: 20060901. Hoffman L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012 Mar;35(2):269-77. PMID: 21932095. Spiekerkoetter U et al. Tandem mass spectrometry screening for very long-chain acyl-CoA dehydrogenase deficiency: the value of second-tier enzyme testing. J Pediatr. 2010 Oct;157(4):668-73. PMID: 20547398. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 366 of the ACADVL protein (p.Arg366His). This variant is present in population databases (rs112406105, gnomAD 0.01%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 20060901, 24263034, 27246109). This variant is also known as p.Arg326His. ClinVar contains an entry for this variant (Variation ID: 203580). 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%. This variant disrupts the p.Arg366 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8845838, 9973285, 21932095; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 27, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2020	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16488171, 26385305, 20060901, 24263034, 27246109, 25456746, 28755359, 28871440, 31589614, 32558070, 32528171, 9973285) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.99
MVP		1.0
MPC		0.86
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs112406105; hg19: chr17-7126471; COSMIC: COSV50039474; COSMIC: COSV50039474;