Variant: NM_000018.4(ACADVL):c.1182+1G>A

CA273937

1622 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 01f2435d-feb0-42c9-80e9-c7af63f2e7f6

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

NM_000018.4:c.1182+1G>A
NM_000018.4(ACADVL):c.1182+1G>A
NC_000017.11:g.7223238G>A
CM000679.2:g.7223238G>A
NC_000017.10:g.7126557G>A
CM000679.1:g.7126557G>A
NC_000017.9:g.7067281G>A
NG_007975.1:g.8405G>A
NG_008391.2:g.1813C>T
ENST00000356839.10:c.1182+1G>A
ENST00000322910.9:c.*1137+1G>A
ENST00000350303.9:c.1116+1G>A
ENST00000356839.9:c.1182+1G>A
ENST00000542255.6:n.40+1G>A
ENST00000543245.6:c.1251+1G>A
ENST00000578579.2:n.131+1G>A
ENST00000578824.5:n.598+1G>A
ENST00000579425.5:n.206+1G>A
ENST00000579546.1:n.19+1G>A
ENST00000583858.5:n.211+1G>A
ENST00000585203.6:n.390+1G>A
NM_000018.3:c.1182+1G>A
NM_001033859.2:c.1116+1G>A
NM_001270447.1:c.1251+1G>A
NM_001270448.1:c.954+1G>A
NM_001033859.3:c.1116+1G>A
NM_001270447.2:c.1251+1G>A
NM_001270448.2:c.954+1G>A

Likely Pathogenic

• Met criteria codes: PVS1_Moderate PM2_Supporting PM3_Supporting PP4_Moderate

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1182+1G>A variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 11. It is predicted to cause skipping of biologically-relevant-exon 11/20, resulting in an in-frame deletion (removes amino acids 360-394) that is predicted to escape nonsense mediated decay (PVS1_Moderate). The prediction of exon 11 skipping was confirmed by RT-PCR of fibroblasts from an individual homozygous for this variant; however, no VLCAD protein was detected (PMID:7479827). At least one patient with this variant displayed increased C14:1 acylcarnitines and reduced VLCAD activity in fibroblasts, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 23480858). This variant has been described in individuals identified by newborn screen, but this information is insufficient to use toward classification (PMID:26385305, 21932095). This variant has been described in affected individuals in the homozygous state and not confirmed in trans to a distinct variant of uncertain significance (PM3_Supporting; PMID: 7479827, 27209629, 23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006154 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PP4_Moderate, PM3_Supporting, PM2_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021).

Met criteria codes

• PVS1_Moderate: The c.1182+1G>A variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 11. It is predicted to cause skipping of biologically-relevant-exon 11/20, resulting in an in-frame deletion (removes amino acids 360-394) that is predicted to escape nonsense mediated decay (PVS1_Moderate).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006154 in African/African American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PM3_Supporting: This variant has been detected in the homozygous state in at least one individual (PMID: 7479827). Detected not confirmed in trans to VUS (PMID: 21932095, 27209629)
• PP4_Moderate: At least one patient with this variant displayed increased C14:1 acylcarnitines and reduced VLCAD activity in fibroblasts, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMID: 23480858)