rs148584617

Variant names:

• chr17-7224973-G-A
• rs148584617
• NM_000018.4:c.1844G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7224973-G-A
• chr17-7224973-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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:7 B:12
• Conservation: PhyloP100: 0.0450
• Publications: 18 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 VariationId is 195448.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 2165 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1844G>A	p.Arg615Gln	missense_variant	Exon 20 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1844G>A	p.Arg615Gln	missense_variant	Exon 20 of 20	1	NM_000018.4	ENSP00000349297.5

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

GnomAD2 exomes AF: 0.00281 AC: 706 AN: 251176 AF XY: 0.00297

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 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

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 303 AN: 26136

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

South Asian (SAS) AF: 0.00217 AC: 187 AN: 86256

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53326

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.00304 AC: 3381 AN: 1112008

Other (OTH) AF: 0.00308 AC: 186 AN: 60394

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

African (AFR) AF: 0.000963 AC: 40 AN: 41558

American (AMR) AF: 0.00399 AC: 61 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68016

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00360 Hom.: 7

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:7 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

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

Jun 19, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2014

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 27, 2023

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:3 Benign:5

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACADVL: BP4, BS2 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 05, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27884173, 21932095, 27209629, 10077518, 17999356, 34485012, 32778825, 34426522, 35281663, 35626289, 26453363, 25087612, 30194637, 28755359, 38651394) -

Feb 23, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Dec 31, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 0.0029 in 1614080 control chromosomes (22 homozygotes), predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0029).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). These report(s) do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. Residual enzymatic activities in compound heterozygous individuals carrying pathogenic variants in trans ranged from 21%, to 40% or 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). The following publications have been ascertained in the context of this evaluation (PMID: 27884173, 21378393, 26453363, 17999356, 21932095, 34426522, 28755359, 27209629). ClinVar contains an entry for this variant (Variation ID: 195448). Based on the evidence outlined above, the variant was classified as likely benign. -

ACADVL-related disorder Benign:1

Aug 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
DEOGEN2	Benign	0.14	.;T;.
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
MutationAssessor	Benign	0.51	.;N;.
PhyloP100		0.045
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
Mutation Taster		=94/6	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: rs148584617; hg19: chr17-7128292; COSMIC: COSV106081352; COSMIC: COSV106081352;