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]

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

CA397723954

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM2_Supporting PP3

PS3 PP4 PM3_Supporting PM1 PM5

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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).

PM2_Supporting

Not in gnomAD or ExAC

PP3

REVEL score of 0.893 (>0.75)

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.

Approved on: 2022-07-28

Published on: 2022-07-28

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