Variant: NM_000018.4(ACADVL):c.266del (p.Pro89fs)

CA8337611

552361 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 66cc33f4-9274-41ae-89f4-b07a919f4d29

HGVS expressions

NM_000018.4:c.266del
NM_000018.4(ACADVL):c.266del (p.Pro89fs)
NC_000017.11:g.7220665del
CM000679.2:g.7220665del
NC_000017.10:g.7123984del
CM000679.1:g.7123984del
NC_000017.9:g.7064708del
NG_007975.1:g.5832del
NG_008391.2:g.4388del
ENST00000356839.10:c.266del
ENST00000322910.9:c.*221del
ENST00000350303.9:c.200del
ENST00000356839.9:c.266del
ENST00000543245.6:c.335del
ENST00000577191.5:n.343del
ENST00000577433.5:n.474del
ENST00000577857.5:n.229-101del
ENST00000578269.5:n.713del
ENST00000578421.1:n.474del
ENST00000579286.5:n.447del
ENST00000579886.2:c.201+139del
ENST00000580263.5:n.430del
ENST00000581562.5:n.313del
ENST00000582056.5:n.356del
ENST00000582166.1:n.154del
ENST00000582356.5:n.465del
ENST00000583312.5:c.266del
ENST00000584103.5:c.266del
NM_000018.3:c.266del
NM_001033859.2:c.200del
NM_001270447.1:c.335del
NM_001270448.1:c.38del
NM_001033859.3:c.200del
NM_001270447.2:c.335del
NM_001270448.2:c.38del

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PM2_Supporting PVS1

• Not Met criteria codes: PP4 PM3

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

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).

Met criteria codes

• PM2_Supporting: PM2_Supporting is met. 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).
• PVS1: PVS1 is met. 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).

Not Met criteria codes

• PP4: PP4 at any strength is not met. 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).
• PM3: PM3 at any strength is not met. This variant has been detected in a heterozygous state in 1 individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency.; a second pathogenic or likely pathogenic variant was not clearly reported (PMID: 26385305).

Approved on: 2022-04-06

Published on: 2022-04-06