Variant: NM_000018.4(ACADVL):c.1316G>A (p.Gly439Asp)

CA312270

203582 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 010f7412-b0c2-4806-bc4d-efc43d4c4586

Approved on: 2025-04-16

Published on: 2025-04-16

HGVS expressions

NM_000018.4:c.1316G>A
NM_000018.4(ACADVL):c.1316G>A (p.Gly439Asp)
NC_000017.11:g.7223859G>A
CM000679.2:g.7223859G>A
NC_000017.10:g.7127178G>A
CM000679.1:g.7127178G>A
NC_000017.9:g.7067902G>A
NG_007975.1:g.9026G>A
NG_008391.2:g.1192C>T
NG_033038.1:g.15686C>T
ENST00000356839.10:c.1316G>A
ENST00000322910.9:c.*1271G>A
ENST00000350303.9:c.1250G>A
ENST00000356839.9:c.1316G>A
ENST00000542255.6:c.174G>A
ENST00000543245.6:c.1385G>A
ENST00000578711.1:n.355G>A
ENST00000579425.5:n.340G>A
ENST00000579546.1:c.153G>A
ENST00000583074.5:n.35G>A
ENST00000583850.5:n.91G>A
ENST00000583858.5:c.345G>A
ENST00000585203.6:n.523+1G>A
NM_000018.3:c.1316G>A
NM_001033859.2:c.1250G>A
NM_001270447.1:c.1385G>A
NM_001270448.1:c.1088G>A
NM_001033859.3:c.1250G>A
NM_001270447.2:c.1385G>A
NM_001270448.2:c.1088G>A

Pathogenic

• Met criteria codes: PS3_Supporting PP2_Moderate PP3_Strong PM3_Supporting PM2_Supporting PM1 PP4_Moderate

• Not Met criteria codes: PM5

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1316G>A variant in ACADVL has been reported in three individuals with very long chain acyl-CoA dehydrogenase deficiency in the literature with either significantly reduced VLCAD activity or increased C14:1 acylcarnitine levels, two displaying both phenotypes at once (PP4_strong; PMIDs: 31031081, 23480858, 17999356). In these same probands, the variant was detected three times not confirmed in-trans with several different variants including the pathogenic variant c.848T>C (PM3_supporting; PMIDs: 31031081, 23480858, 17999356). Fibroblast analysis and E. coli transfected with constructs harboring the variant both showed significantly deficient enzyme activity (PS3_supporting; PMIDs: 23480858, 17999356). This variant has a MAF of 0.00005012 in the East Asian population (PM2_supporting; https://gnomad.broadinstitute.org). The variant is located in a well-studied Gly-Gly-x-Gly motif which is critical for the protein's dimer interaction with FAD (PM1; PMID: 20060901). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: PP4; PM3; PS3; PM2; PM1; PP3

Met criteria codes

• PS3_Supporting: Two separate functional assays, both E. coli expression using mutagenesis and patient-derived fibroblasts, showed significantly deficient enzyme activity resulting from this variant (0% activity and 30% activity (compound het with a likely mild variant) respectively). The latter had many other variants and several controls with the former having two WT controls but no known benign variants or null controls. Therefore, this evidence earns PS3_Supporting for a broadly accepted and previously validated assay.
• PP2_Moderate: Out of 700 missense variants reported in ClinVar only 8 are reported as benign or likely benign
• PP3_Strong: REVEL score at 0.964 (>0.75), Polyphen (1), Varity (0.99), AlphaMissense (Moderate - 0.953), etc
• PM3_Supporting: Detected not confirmed in-trans with the pathogenic variant ClinVarID:21025 (p.V283A) among others not evaluated. 0.5 Points.
• PM2_Supporting: Variant in gnomAD East Asian population at 0.00005012 (<0.001)
• PM1: This variant is located in a highly conserved domain that interacts with FAD. In particular, a substitution with an acidic residue in this well-established Gly-Gly-x-Gly motif would likely cause disruption of the dimer interaction with FAD.
• PP4_Moderate: This variant appears in three probands in the literature, two of which have elevated C14:1 levels and all of which have significantly deficient VLCAD enzyme activity consistent with the disorder.

Not Met criteria codes

• PM5: No other known pathogenic variants.