Variant: NM_000018.4:c.910G>A

CA397723954

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 5409e03a-3e41-44f2-99dc-6b896bba0430

Approved on: 2022-07-28

Published on: 2022-07-28

HGVS expressions

NM_000018.4:c.910G>A
NC_000017.11:g.7222698G>A
CM000679.2:g.7222698G>A
NC_000017.10:g.7126017G>A
CM000679.1:g.7126017G>A
NC_000017.9:g.7066741G>A
NG_007975.1:g.7865G>A
NG_008391.2:g.2353C>T
ENST00000356839.10:c.910G>A
ENST00000322910.9:c.*865G>A
ENST00000350303.9:c.844G>A
ENST00000356839.9:c.910G>A
ENST00000543245.6:c.979G>A
ENST00000578824.5:n.59G>A
ENST00000581378.5:n.628G>A
ENST00000582379.1:n.294G>A
NM_000018.3:c.910G>A
NM_001033859.2:c.844G>A
NM_001270447.1:c.979G>A
NM_001270448.1:c.682G>A
NM_001033859.3:c.844G>A
NM_001270447.2:c.979G>A
NM_001270448.2:c.682G>A

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

• Not Met criteria codes: PS3 PP4 PM3_Supporting PM1 PM5

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.910G>A variant in ACADVL is a missense variant predicted to cause a substitution of alanine by threonine at amino acid 304 (p.Ala304Thr). This variant has been reported in the literature in one individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency with reduced VLCAD activity and beta oxidation flux, but at levels that do not currently meet the ACADVL Variant Curation Expert Panel specifications for PP4 (PMID: 17999356). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.893, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is 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: PM2_Supporting, PP3 (ACADVL specifications version 1; approved November 8, 2021).

Met criteria codes

• PP3: REVEL score of 0.893 (>0.75)
• PM2_Supporting: Not in gnomAD or ExAC

Not Met criteria codes

• PS3: β-oxidation flux measured in a proband compound heterozygous for this mutation showed a value of 1.43 ± 0.18 nmol 3H FA/h/mg protein, 30% of wild-type values (4.8 ± 1.0 nmol 3H FA/h/mg protein; n=5). This assay was performed with a variety of unaffected controls and known pathogenic variants. The authors assert that the majority of the residual enzyme activity results from this variant, which is supported by the fibroblast's 300% increase in activity when treated with bezafibrate. Overall, this assay only contributes minimal evidence to support this variant's pathogenicity and is patient-derived information which does not fit in this category.
• PP4: Proband has significantly reduced VLCAD enzyme activity in fibroblasts (Group values of 0.4 to 3.3 nmol/min/mg protein; reference 11±1.9 nmol/min/mg protein, n=3). Additionally, β-oxidation flux measured in a proband showed a value of 1.43 ± 0.18 nmol 3H FA/h/mg protein, 30% of wild-type values (4.8 ± 1.0 nmol 3H FA/h/mg protein; n=5). As this does not meet the 27% requirement, this proband does not meet PP4.
• PM3_Supporting: Seen not confirmed in-trans with ClinVar:203582 (p.Gly439Asp) 0.5 Points. Needs to be reviewed as the proband seems to not meet PP4 AND variant is downgraded to LP, so would not be enough for PM3_supporting regardless.
• PM1: The variant is located distally from FAD and substrate binding and does not significantly structurally affect the protein when altered.
• PM5: Another amino acid change in the same position has been asserted pathogenic: CA397723957 (p.Ala304Val). However, this has only one published case and not enough information to be considered likely pathogenic by these guidelines.