rs28934585

chr17-7220519-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000018.4(ACADVL):c.194C>T(p.Pro65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,614,186 control chromosomes in the GnomAD database, including 494 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (248 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (246 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: -1.74

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034344792).
• BP6: Variant 17-7220519-C-T is Benign according to our data. Variant chr17-7220519-C-T is described in ClinVar as [Benign]. Clinvar id is 38798.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-7220519-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.194C>T	p.Pro65Leu	missense_variant	3/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.194C>T	p.Pro65Leu	missense_variant	3/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4888 AN: 152190 Hom.: 247 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.00823 AC: 2069 AN: 251436 Hom.: 102 AF XY: 0.00600 AC XY: 816 AN XY: 135916

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00323 AC: 4719 AN: 1461878 Hom.: 246 Cov.: 33 AF XY: 0.00278 AC XY: 2023 AN XY: 727240

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.00635

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00798

GnomAD4 genome AF: 0.0321 AC: 4895 AN: 152308 Hom.: 248 Cov.: 33 AF XY: 0.0311 AC XY: 2315 AN XY: 74472

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00985 Hom.: 67

Bravo AF: 0.0362

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0992 AC: 437

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0105 AC: 1273

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Benign:6

Benign, 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.194C>T (NP_000009.1:p.Pro65Leu) [GRCH38: NC_000017.11:g.7220519C>T] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Mar 08, 2022	The c.194C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 65 (p.Pro65Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1129 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). Palmitoyl-CoA dehydrogenase activity in VLCAD-null fibroblasts transfected with c.194C>T cDNA showed activity comparable to the cells transfected with wild-type cDNA indicating that this variant does not impact protein function (PMID: 10790204, BS3_supporting). The computational predictor REVEL gives a score of 0.276, 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 benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BS3_supporting, BP4 (VCEP specifications v2.0, approved on 09/16/2021). -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 09, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Oct 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	3.9
Dann	Benign	0.71
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.40	T;T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.8e-8	A;A;A
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.047	D;.;.;.;.
Sift4G	Benign	0.14	T;T;T;T;D
Polyphen		0.019	.;B;.;.;.
Vest4		0.11
MPC		0.20
ClinPred		0.017	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.025
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28934585; hg19: chr17-7123838; COSMIC: COSV50035622; COSMIC: COSV50035622;