rs150140386

chr17-7222854-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Strong BS2

The NM_000018.4(ACADVL):c.1066A>G(p.Ile356Val) variant causes a missense change. The variant allele was found at a frequency of 0.000514 in 1,612,152 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I356T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5 B:6
• Conservation: PhyloP100: 4.01

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 -10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000018.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.00963226).
• BP6: Variant 17-7222854-A-G is Benign according to our data. Variant chr17-7222854-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 193541.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=4}.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1066A>G	p.Ile356Val	missense_variant	10/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1066A>G	p.Ile356Val	missense_variant	10/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152126 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00906

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000850 AC: 213 AN: 250672 Hom.: 2 AF XY: 0.000590 AC XY: 80 AN XY: 135522

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000296 AC: 432 AN: 1459908 Hom.: 1 Cov.: 32 AF XY: 0.000240 AC XY: 174 AN XY: 726248

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000614

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74444

Gnomad4 AFR AF: 0.00908

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000540 Hom.: 2

Bravo AF: 0.00317

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:5 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 20, 2022	The ACADVL c.1066A>G; p.Ile356Val variant (rs150140386) is reported in the literature in multiple individuals with abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, though its clinical significance was not determined (Miller 2015). This variant has been observed in asymptomatic individuals with abnormal acylcarnitine profiles who also carried a pathogenic variant (Pena 2016, Tangeraas 2020). Additionally, it has been reported in a symptomatic individual with VLCAD deficiency (Rovelli 2019). This variant is reported in ClinVar (Variation ID: 193541). It is found in the African/African American population with an allele frequency of 0.98% (244/24934 alleles, including 3 homozygotes) in the Genome Aggregation Database. The isoleucine at codon 356 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.621). Due to conflicting information, the significance of the p.Ile356Val variant is uncertain at this time. References: Miller M et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. 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. PMID: 27209629. Rovelli V et al. Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73. PMID: 31031081. Tangeraas T et al. Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses. Int J Neonatal Screen. 2020 Jun 27;6(3):51. PMID: 33123633. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
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.1066A>G (NP_000009.1:p.Ile356Val) [GRCH38: NC_000017.11:g.7222854A>G] 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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2023	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Apr 11, 2023	The c.1066A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 356 (p.Ile356Val). Several individuals with this variant were identified by newborn screen, but this information is insufficient to use toward classification (PMID: 30194637, 26385305, 23867825, 31031081, 27209629). One individual did display C14:1 level of 0.83, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 31031081). At least one of these individuals carried an additional likely pathogenic variant not confirmed to be in trans, but this does not meet the criteria to be counted toward PM3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009786 in the African population with 3 total homozygotes, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (>=0.007) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.621, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. In summary, this variant meets the criteria to be classified as variant of uncertain significance 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, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on April 11, 2023. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 27, 2021	NM_000018.3(ACADVL):c.1066A>G(I356V) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. I356V has been observed in cases with relevant disease (PMID: 20480395, 23867825, 27209629, 30194637, 33123633). Functional assessments of this variant are not available in the literature. I356V has been observed in population frequency databases (gnomAD: AFR 0.98%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1066A>G(I356V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	Variant summary: ACADVL c.1066A>G (p.Ile356Val) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 250672 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1066A>G has been reported in the literature in individuals with abnormal newborn screening results, hypoglycemia or fatty acid oxidation defects (Ndukwe_2013, Miller_2015, Pena_2016, Hesse_2018, Tangeraas_2020). These reports do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Hesse_2018). Three ClinVar submitters (evaluation after 2014) cite the variant as benign and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2021

This variant is associated with the following publications: (PMID: 23867825, 26385305, 27209629, 31031081) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Uncertain	0.63	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.73	N;.;N
REVEL	Uncertain	0.62
Sift	Benign	0.067	T;.;T
Sift4G	Benign	0.062	T;T;T
Polyphen		0.98, 0.56	.;D;P
Vest4		0.77
MVP		0.77
MPC		0.22
ClinPred		0.018	T
GERP RS		5.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.55
gMVP		0.55

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: rs150140386; hg19: chr17-7126173;