rs1057516979

Positions:

• chr17-7220794-TAA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The c.308_309del (p.Lys103Argfs*20) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity; a second distinct pathogenic or likely pathogenic variant in ACADVL was not reported in this individual (PMID:26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC 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: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#2; 05-00-2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041859/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADVL NM_000018.4 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 1.20

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 Likely_pathogenic. Variant got 9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.308_309del	p.Lys103ArgfsTer20	frameshift_variant	5/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.308_309del	p.Lys103ArgfsTer20	frameshift_variant	5/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5

Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	May 10, 2022	The c.308_309del (p.Lys103Argfs*20) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity; a second distinct pathogenic or likely pathogenic variant in ACADVL was not reported in this individual (PMID: 26385305). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC 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: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#2; 05-00-2022). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 11, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371068). This premature translational stop signal has been observed in individual(s) with abnormal newborn screening results suggestive of VLCADD (PMID: 26385305). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys103Argfs*20) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2024	- -
Pathogenic, 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.308_309delAA (NP_000009.1:p.Lys103ArgfsTer20) [GRCH38: NC_000017.11:g.7220796_7220797del] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2022

Reported in a single allele from a cohort of patients referred for analysis of the ACADVL gene after a positive newborn screening result (Miller MJ et al. 2015); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26385305, 27535533) -

Computational scores

Source: dbNSFP v4.3

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: rs1057516979; hg19: chr17-7124113;