rs771808680

Positions:

• chr17-7220662-TC-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.266del variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 4/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The variant has been identified in at least one individual identified by abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency without an additional ACADVL variant identified or follow-up plasma acylcarnitines (PMID:26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005437 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (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 (ACADVL VCEP specifications v2.0; Approved on 12/14/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337611/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADVL ENST00000356839.10 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: -0.557

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.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.266del	p.Pro89HisfsTer28	frameshift_variant	4/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.266del	p.Pro89HisfsTer28	frameshift_variant	4/20	1	NM_000018.4	ENSP00000349297	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

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.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5

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.266delC (NP_000009.1:p.Pro89HisfsTer28) [GRCH38: NC_000017.11:g.7220665del] 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 -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Apr 06, 2022	The c.266del variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 4/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The variant has been identified in at least one individual identified by abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency without an additional ACADVL variant identified or follow-up plasma acylcarnitines (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005437 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (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 (ACADVL VCEP specifications v2.0; Approved on 12/14/2021). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552361). This premature translational stop signal has been observed in individual(s) with newborn screening results suggestive of very long chain acyl-coA dehydrogenase deficiency (PMID: 26385305). This variant is present in population databases (rs771808680, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Pro89Hisfs*28) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs771808680; hg19: chr17-7123981;