Variant: NM_000018.4(ACADVL):c.881G>A (p.Gly294Glu)

CA312257

203575 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 4c78de8e-d637-46b4-8400-24ad408c69df

Approved on: 2023-03-28

Published on: 2023-03-28

HGVS expressions

NM_000018.4:c.881G>A
NM_000018.4(ACADVL):c.881G>A (p.Gly294Glu)
NC_000017.11:g.7222669G>A
CM000679.2:g.7222669G>A
NC_000017.10:g.7125988G>A
CM000679.1:g.7125988G>A
NC_000017.9:g.7066712G>A
NG_007975.1:g.7836G>A
NG_008391.2:g.2382C>T
ENST00000356839.10:c.881G>A
ENST00000322910.9:c.*836G>A
ENST00000350303.9:c.815G>A
ENST00000356839.9:c.881G>A
ENST00000543245.6:c.950G>A
ENST00000578824.5:n.30G>A
ENST00000581378.5:n.599G>A
ENST00000582379.1:n.265G>A
NM_000018.3:c.881G>A
NM_001033859.2:c.815G>A
NM_001270447.1:c.950G>A
NM_001270448.1:c.653G>A
NM_001033859.3:c.815G>A
NM_001270447.2:c.950G>A
NM_001270448.2:c.653G>A

Uncertain Significance

• Met criteria codes: PM3_Supporting PM2_Supporting PP3 PP4_Moderate

• Not Met criteria codes: PM5 PM1 PS3 PS1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.881G>A variant in ACADVL is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 294 (p.Gly294Glu). At least two patients with this variant displayed low very long chain acyl-CoA dehydrogenase (VLCAD) enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8739957, 12208138). This variant has been detected in at least three patients with clinically diagnosed VLCAD deficiency. Two of these individuals were compound heterozygous for this variant and a likely pathogenic variant, neither confirmed to be in trans (PM3_Supporting; PMID: 25737446,17999356). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL VCEP threshold (0.001) for PM2_supporting, meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.919, which is above the threshold of 0.75, evidence that correlates with impact to VLCAD function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_moderate, PM2_supporting, PM3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021). This variant was originally curated April 12, 2022 and the recurated classification was approved by the expert panel on March 28, 2023.

Met criteria codes

• PM3_Supporting: - In unconfirmed trans with c.553G>A (p.G185S) - PMID 17999356, PMID 25737446 (cDNA descriptor not used in latter paper) 0.5 points, 2 unconfirmed in trans to LP variant Other variants not approved pathogenic or likely pathogenic, added to tracking spreadsheet - In unconfirmed trans with c.869G>A (p.G250D) - PMID 12208138
• PM2_Supporting: MAF <0.1% in gnomAD
• PP3: REVEL score is >0.75
• PP4_Moderate: G294E: acyl-CoA dehydrogenase activity was "consistent with a defect in VLCAD" (PMID 8739957). G294E (case F10): VLCAD activity was 10% of normal controls (PMID 12208138).

Not Met criteria codes

• PM5: No identification of another pathogenic variant at this amino acid residue.
• PM1: -G294E is at a residue that is conserved in other human acyl-CoA dehydrogenases (PMID 8739957). Otherwise, no mutational hot/spot or well-established functional domain at this residue is identified in the literature in accordance with VCEP criteria.
• PS3: G294E shows reduced beta-oxidation flux in patient fibroblasts and is characterized as a severe mutation in PMID 17999356 (however, since this is patient cells lines, this study is not applied to PS3 per VCEP criteria).
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline