rs148584617

chr17-7224973-G-Achr17-7224973-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000018.4(ACADVL):c.1844G>A(p.Arg615Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,080 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (20 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:8 B:10
• Conservation: PhyloP100: 0.0450

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000018.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0066580176).
• BP6: Variant 17-7224973-G-A is Benign according to our data. Variant chr17-7224973-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 195448.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-7224973-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00292 (4264/1461790) while in subpopulation MID AF= 0.0133 (77/5768). AF 95% confidence interval is 0.0109. There are 20 homozygotes in gnomad4_exome. There are 2165 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1844G>A	p.Arg615Gln	missense_variant	20/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1844G>A	p.Arg615Gln	missense_variant	20/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00281 AC: 706 AN: 251176 Hom.: 4 AF XY: 0.00297 AC XY: 404 AN XY: 135832

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00292 AC: 4264 AN: 1461790 Hom.: 20 Cov.: 35 AF XY: 0.00298 AC XY: 2165 AN XY: 727208

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00217

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.00304

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74464

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00312

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00387 Hom.: 4

Bravo AF: 0.00271

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00284 AC: 345

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00528

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:8 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:1 Uncertain:4 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	The ACADVL p.Arg615Gln variant (rs148584617; ClinVar variation ID: 195448) has been previously identified by our laboratory, and is described in the literature in multiple patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (Gobin-Limballe 2007, Mathur 1999, Hoffmann 2012, Diekman 2016, Pena 2016). However the exact contribution of this variant to the clinical presentation of these patients is unclear. The enzyme activity in cells isolated from patients with VCLAD was reported to range from 21% of control activity (Hoffmann 2012) to 40% (Diekman 2016) to be indistinguishable from control activity (Gobin-Limballe 2007) for p.Arg615Gln when in trans with different ACADVL variants. And at least one study identified this variant in two individuals who failed newborn screening, but had not developed symptoms at age 2 (Diekman 2016). Furthermore, this variant is found in the general population with an overall allele frequency of 0.27% (758/282,554 alleles, including 4 homozygotes) in the Genome Aggregation Database. The arginine at codon 615 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.397). Due to conflicting information, the clinical significance of the p.Arg615Gln variant is uncertain at this time. References: Diekman E et al. The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency. JIMD Rep. 2016;27:101-6. PMID: 26453363. Gobin-Limballe et al. Genetic basis for correction of very-long-chain acyl-coenzyme A dehydrogenase deficiency by bezafibrate in patient fibroblasts: toward a genotype-based therapy. Am J Hum Genet. 2007; 81(6): 1133-1143. PMID: 17999356. Hoffmann et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2): 269-277. PMID: 21932095. Mathur et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999; 99(10): 1337-1343. PMID: 10077518. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PubMed: 27209629. Tabor et al. Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Am J Hum Genet. 2014; 95(2): 183-193. PubMed: 25087612. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 13, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 19, 2020	- -
Uncertain significance, 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.1844G>A (NP_000009.1:p.Arg615Gln) [GRCH38: NC_000017.11:g.7224973G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Jun 27, 2023	The c.1844G>A variant in ACADVL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 615 (p.Arg615Gln), also called Arg575Gln in the processed peptide. The variant has been identified in individuals identified by positive newborn screen, or identified in individuals with suspected very long chain acyl-CoA dehydrogenase (VLCAD) deficiency that was not confirmed biochemically, but this information is insufficient to use toward classification (PMID: 10077518, 17999356, 27209629, 21932095, 26453363). The variant has been reported to occur in individuals who also carried a distinct ACADVL variant not confirmed in trans; however, since none of these individuals met PP4, the ACADVL VCEP could not count these toward PM3 evidence (PMID: 17999356, 21932095, 27209629). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.003654 in the European (non-Finnish) population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (>=0.0035) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.397, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, BP4 (ACADVL VCEP specifications version 1; approved November 8, 2021). -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not provided Uncertain:3 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2023	BS1 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ACADVL: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28755359, 27884173, 21932095, 27209629, 10077518, 17999356, 30194637, 26453363, 34485012, 32778825, 34426522, 35281663, 35626289) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 10, 2022

Variant summary: ACADVL c.1844G>A (p.Arg615Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251176 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. An additional 5 homozygous occurrences have been reported in the literature in individuals with lack of phenotype (Abouelhoda_2016, Kars_2021). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) phenotype (0.0029), suggesting that the variant is a benign polymorphism. c.1844G>A has been reported in the literature as a biallelic genotype in individuals with mild forms of VLCAD deficiency and in individuals identified through Newborn Screening who were asymptomatic (e.g. Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016, Pena_2016). Residual enzymatic activities in compound heterozygous individuals carrying pathogenic variants in trans ranged from 21%, to 40% and up to similar activity to controls (Gobin-Limballe_2007, Bastin_2011, Hoffmann_2012, Diekman_2016). In one simple heterozygous individual with the variant, residual enzymatic activity was measured at 39% (Hoffmann_2012), with the authors concluding from their study that individuals with a residual enzyme activity >20% present with a biochemical phenotype but likely remain asymptomatic throughout life. The variant was found to co-occur in cis with a pathogenic variant in one homozygous and one compound heterozygous individuals who had symptoms of VLCAD (Merinero_2018). Eleven ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, and four as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	14
Dann	Benign	0.90
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.63	N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.49	T;.;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.033, 0.020	.;B;B
Vest4		0.66
MVP		0.63
MPC		0.22
ClinPred		0.0040	T
GERP RS		0.89
Varity_R		0.11
gMVP		0.58

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: rs148584617; hg19: chr17-7128292;