Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA8337581

553583 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Approved on: 2022-09-23

Published on: 2022-09-23

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"

PVS1 PM2_Supporting

BP2 BP7 PS1 PP3 PP4 PM4 PM5 PM3 PM1

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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.

PVS1

PVS1 is met; Variant predicted to result in a frameshift at exon 3 of predominant transcript; >10% protein excluded ; predicted to undergo NMD

PM2_Supporting

PM2_Supporting is met; Variant described as g.7123831del is observed 4/282792 alleles in gnomAD; no homozygotes

BP2

BP2 is not met; Variant has not been observed in cis with a pathogenic variant in ACADVL.

BP7

BP7 is not met; Variant is null variant.

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.

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

Curation History

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