Variant: NM_000018.4(ACADVL):c.192del (p.Lys64fs)

CA8337581

553583 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 16e07036-bca8-4df0-b774-3f934bb31e80

HGVS expressions

NM_000018.4:c.192del
NM_000018.4(ACADVL):c.192del (p.Lys64fs)
NC_000017.11:g.7220517del
CM000679.2:g.7220517del
NC_000017.10:g.7123836del
CM000679.1:g.7123836del
NC_000017.9:g.7064560del
NG_007975.1:g.5684del
NG_008391.2:g.4539del
ENST00000356839.10:c.192del
ENST00000322910.9:c.*147del
ENST00000350303.9:c.139-87del
ENST00000356839.9:c.192del
ENST00000543245.6:c.261del
ENST00000577191.5:n.269del
ENST00000577433.5:n.326del
ENST00000577857.5:n.229-249del
ENST00000578269.5:n.565del
ENST00000578421.1:n.326del
ENST00000579286.5:n.299del
ENST00000579886.2:c.192del
ENST00000580263.5:n.282del
ENST00000581562.5:n.239del
ENST00000582056.5:n.282del
ENST00000582166.1:n.80del
ENST00000582356.5:n.317del
ENST00000583312.5:c.192del
ENST00000584103.5:c.192del
NM_000018.3:c.192del
NM_001033859.2:c.139-87del
NM_001270447.1:c.261del
NM_001270448.1:c.-37del
NM_001033859.3:c.139-87del
NM_001270447.2:c.261del
NM_001270448.2:c.-37del

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: PM4 PM5 PM3 PM1 BP7 BP2 PS1 PP3 PP4

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.192del (p.Lys64fs) variant in ACADVL is a frameshift predicted to cause a premature stop codon in biologically relevant exon 3/20 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 0.0001603 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency has been reported with this variant (PMID: 26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting.

Met criteria codes

• PM2_Supporting: PM2_Supporting is met; Variant described as g.7123831del is observed 4/282792 alleles in gnomAD; no homozygotes
• PVS1: PVS1 is met; Variant predicted to result in a frameshift at exon 3 of predominant transcript; >10% protein excluded ; predicted to undergo NMD

Not Met criteria codes

• PM4: PM4 is not met; Variant predicted to result in frameshift.
• PM5: PM5 is not met; Variant is null variant
• PM3: PM3 is not met; Variant reported in one NBS+ or presumptive NBS case as het with no reported second ACADVL allele (PMID: 26385305). Counsyl reports variant in clinical testing for VLCADD but no zygosity or number of cases mentioned.
• PM1: PM1 is not met; Variant is a null variant; PM1 reserved for missense
• BP7: BP7 is not met; Variant is null variant.
• BP2: BP2 is not met; Variant has not been observed in cis with a pathogenic variant in ACADVL.
• PS1: PS1 is not met; Variant is null variant
• PP3: PP3 is not met; Variant is null variant; see PVS1
• PP4: PP4 is not met; Uncertain if the one case referred to in PMID: 26385305 is NBS+ or presumptive NBS with no clinical and/or biochemical information.

Approved on: 2022-09-23

Published on: 2022-09-23