17-7222807-G-T

Position:

• chr17-7222807-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1019G>T (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of glycine by valine at amino acid 340 (p.Gly340Val). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID:26385305, 27246109). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as a 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: PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA287437667/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 8.54

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 Uncertain_significance. Variant got 2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.1019G>T	p.Gly340Val	missense_variant	10/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.1019G>T	p.Gly340Val	missense_variant	10/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461622 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 23, 2018	- -
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.1019G>T (NP_000009.1:p.Gly340Val) [GRCH38: NC_000017.11:g.7222807G>T] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant dose not meet any evidence codes reported in the ACMG guidelines. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 20, 2022	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 340 of the ACADVL protein (p.Gly340Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 26385305, 27246109). ClinVar contains an entry for this variant (Variation ID: 426177). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2019	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed as heterozygous in multiple patients with abnormal newborn screening results for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in whom a second pathogenic variant was not identified in the ACADVL gene; no additional clinical information was provided for these patients (Miller et al. 2015; Evans et al., 2016).; This variant is associated with the following publications: (PMID: 26385305, 27246109) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 27, 2017	The ACADVL c.1019G>T;p.Gly340Val variant has been described in the medical literature in individuals identified by newborn screen and at least one reportedly symptomatic adult (Evans 2016, Miller 2015, Olpin 2017). The variant is listed in the ClinVar database (Variation ID: 426177) but not the dbSNP variant database or the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is well conserved across species, located near the active site (McAndrew 2008), and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is considered likely pathogenic. References: 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. McAndrew RP et al. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J Biol Chem. 2008 Apr 4;283(14):9435-43. Miller MJ 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. Olpin SE et al. Fibroblast Fatty-Acid Oxidation Flux Assays Stratify Risk in Newborns with Presumptive-Positive Results on Screening for Very-Long Chain Acyl-CoA Dehydrogenase Deficiency. Int J Neonat Screen. 2017 3(1):2. -

ACADVL-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2023

The ACADVL c.1019G>T variant is predicted to result in the amino acid substitution p.Gly340Val. This variant was detected in at least in six individuals with abnormal newborn screening suggestive of VLCADD. Based on the available literature, it is unclear if another pathogenic variant was detected on the opposite allele (Miller et al. 2015. PubMed ID: 26385305, Evans and Nation. 2016. PubMed ID: 27246109). In sillico structural modeling analysis suggested that this variant is located in close proximity to the VLCAD active site (Miller et al. 2015. PubMed ID: 26385305). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-9.0	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.95
MutPred		0.78		.;Loss of methylation at R341 (P = 0.0536);.;
MVP		1.0
MPC		0.86
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs934797393; hg19: chr17-7126126;