rs753108198

Positions:

• chr17-7222674-CCT-C

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.887_888del (p.Pro296ArgfsTer17) variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has also been reported in patients with phenotypes suggestive of a fatty acid oxidation defect (PMIDs: 10077518, 32778825). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PVS1+PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274249/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ACADVL ENST00000356839.10 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 4.58

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.887_888del	p.Pro296ArgfsTer17	frameshift_variant	10/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.887_888del	p.Pro296ArgfsTer17	frameshift_variant	10/20	1	NM_000018.4	ENSP00000349297	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250254 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461432 Hom.: 0 AF XY: 0.0000234 AC XY: 17 AN XY: 726962

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74418

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:10

Likely pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Jun 13, 2023	The c.887_888del (p.Pro296ArgfsTer17) variant in ACADVL results in a frameshift predicted to cause a premature stop codon in biologically relevant exon 10/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has also been reported in patients with phenotypes suggestive of a fatty acid oxidation defect (PMIDs: 10077518, 32778825). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PVS1+PM2_supporting). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ACADVL NM_000018.3 exon 10 p.Pro296Argfs*17 (c.887_888del): This variant has been reported in the literature in the homozygous or compound heterozygous state in multiple individuals with features of VLCAD deficiency (Schiff 2013 PMID:23480858, Hesse 2018 PMID:30194637, Wang 2019 PMID:31620161). Additionally, enzyme studies on fibroblast samples from two patients showed no detectible residual enzyme activity (Mathur 1999 PMID:10077518, Schiff 2013 PMID:23480858). This variant is present in 0.002% (1/34482) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-7125993-CCT-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or Likely Pathogenic (Variation ID:189008). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 17 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Andresen 1999 PMID:9973285). In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2020	The p.Pro296ArgfsX17 variant in ACADVL has been reported in several individuals with very long chain acyl-CoA dehydrogenase deficiency (VLCADD), including at least 1 homozygous and 3 compound heterozygous individuals (Hesse 2018 PMID 30194637; Roe 2002 PMID:12122118; Wang 2019 PMID:31620161; Mathur 1999 PMID:10077518; Miller 2015 PMID:26385305; Schiff 2013 PMID:23480858). It has also been identified in 2/250254 of the total chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 296 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ACADVL gene is an established disease mechanism in autosomal recessive VLCADD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive VLCADD. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 02, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 08, 2021	- -
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.887_888delCT (NP_000009.1:p.Pro296ArgfsTer17) [GRCH38: NC_000017.11:g.7222675_7222676delCT] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 10077518. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change creates a premature translational stop signal (p.Pro296Argfs*17) 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). This variant is present in population databases (rs753108198, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 23480858, 30194637). ClinVar contains an entry for this variant (Variation ID: 189008). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 01, 2019	Variant summary: ACADVL c.887_888delCT (p.Pro296ArgfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250254 control chromosomes (gnomAD). c.887_888delCT has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Hesse_2018, Mathur_1999, Schiff_2013, Wang_2019). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2014	The c.887_888delCT mutation has been reported previously in association with VLCAD deficiency (Mathur et al., 1999). The deletion causes a frameshift starting with codon Proline 296, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Pro296ArgfsX17. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in ACADVL panel(s). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs753108198; hg19: chr17-7125993;