rs1443151475

Positions:

• chr17-7220160-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PP4_Moderate PM2_Supporting PM3

This summary comes from the ClinGen Evidence Repository: The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 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 at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID:25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA624861220/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ACADVL NM_000018.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: -0.0620

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 Pathogenic. Variant got 13 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.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.104delC	p.Pro35fs	frameshift_variant	2/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.104delC	p.Pro35fs	frameshift_variant	2/20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000219 AC: 3 AN: 137290 Hom.: 0 AF XY: 0.0000267 AC XY: 2 AN XY: 74968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000408

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: 0.0000190

Gnomad OTH exome AF: 0.000244

GnomAD4 exome AF: 0.00000360 AC: 5 AN: 1388036 Hom.: 0 Cov.: 35 AF XY: 0.00000292 AC XY: 2 AN XY: 685150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

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: 0.00000370

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Apr 06, 2022	The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 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 at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID: 25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021). -
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.104delC (NP_000009.1:p.Pro35LeufsTer26) [GRCH38: NC_000017.11:g.7220163delC] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 25834949 . This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Pro35Leufs*26) 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 (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 25834949). ClinVar contains an entry for this variant (Variation ID: 541718). 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	May 06, 2021	Variant summary: ACADVL c.104delC (p.Pro35LeufsX26) 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 2.2e-05 in 137290 control chromosomes. c.104delC has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1999, Knottnerus_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports that enzyme activity in the patient carrying homozygous c.104delC had <10% of normal activity (Knottnerus_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1443151475; hg19: chr17-7123479;