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(ACADVL):c.818G>C (p.Gly273Ala)

CA312255

203574 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 276dab0c-a3e6-4f33-8a05-404d95eb9e28

HGVS expressions

NM_000018.4:c.818G>C

NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala)

NC_000017.11:g.7222242G>C

CM000679.2:g.7222242G>C

NC_000017.10:g.7125561G>C

CM000679.1:g.7125561G>C

NC_000017.9:g.7066285G>C

NG_007975.1:g.7409G>C

NG_008391.2:g.2809C>G

ENST00000356839.10:c.818G>C

ENST00000322910.9:c.*773G>C

ENST00000350303.9:c.752G>C

ENST00000356839.9:c.818G>C

ENST00000543245.6:c.887G>C

ENST00000577191.5:n.990G>C

ENST00000581378.5:c.536G>C

ENST00000582379.1:n.202G>C

NM_000018.3:c.818G>C

NM_001033859.2:c.752G>C

NM_001270447.1:c.887G>C

NM_001270448.1:c.590G>C

NM_001033859.3:c.752G>C

NM_001270447.2:c.887G>C

NM_001270448.2:c.590G>C

Uncertain Significance

PM3_Supporting PP4 PP3 BS1

BA1 PM2 PM1

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala) in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 273 (p. Gly273Ala). The highest population minor allele frequency in gnomAD v3.1.2 is 0.003621 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). At least one patient with this variant displayed an increased C14:1 level, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Supporting, PMID: 24503138), from whom a pathogenic variant was also identified with unknown phase (PM3 point 0.5, PM3_Supporting, PMID: 24503138). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 32778825). The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, PP4_Supporting, PM3_Supporting, PP3)

PM3_Supporting

Co-found with c.848T>C with unknown phase.

PP4

NBS C14:1 Levels from >0.8 μM

PP3

REVEL score was 0.933 which is higher than the 0.75 cutoff for ACADVL

BS1

Highest MAF was 0.003621 in AFR in gnomAD v3.1 which is greater than the ACADVL threshold of 0.0035.

BA1

Highest minor allele frequency was 0.003621 in gnomAD which was not above the ACADVL criteria of 0.007. (A higher value of .00454 was seen in the 1000 genomes project but did not meet the >2000 allele criteria for inclusion)

PM2

The variant allele frequency is above the 0.001 cutoff (0.003621 in AFR in gnomAD v3.1)

PM1

p.G273A is not in a hotspot or functional domain.

Approved on: 2023-09-26

Published on: 2023-09-26

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