Variant: NM_000018.4(ACADVL):c.538G>A (p.Ala180Thr)

CA295584

166641 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: bef919f1-3031-42e2-911a-bf0cd70e9570

Approved on: 2024-04-23

Published on: 2024-04-23

HGVS expressions

NM_000018.4:c.538G>A
NM_000018.4(ACADVL):c.538G>A (p.Ala180Thr)
NC_000017.11:g.7221598G>A
CM000679.2:g.7221598G>A
NC_000017.10:g.7124917G>A
CM000679.1:g.7124917G>A
NC_000017.9:g.7065641G>A
NG_007975.1:g.6765G>A
NG_008391.2:g.3453C>T
ENST00000356839.10:c.538G>A
ENST00000322910.9:c.*493G>A
ENST00000350303.9:c.472G>A
ENST00000356839.9:c.538G>A
ENST00000543245.6:c.607G>A
ENST00000577191.5:n.615G>A
ENST00000577433.5:n.746G>A
ENST00000577857.5:n.354G>A
ENST00000579286.5:n.719G>A
ENST00000579886.2:c.376G>A
ENST00000580365.1:n.269G>A
ENST00000581378.5:c.256G>A
ENST00000581562.5:n.525-354G>A
ENST00000582166.1:n.519G>A
ENST00000583312.5:c.538G>A
ENST00000583760.1:n.320G>A
NM_000018.3:c.538G>A
NM_001033859.2:c.472G>A
NM_001270447.1:c.607G>A
NM_001270448.1:c.310G>A
NM_001033859.3:c.472G>A
NM_001270447.2:c.607G>A
NM_001270448.2:c.310G>A

Likely Pathogenic

• Met criteria codes: PP3 PP4_Moderate PM2_Supporting PM3

• Not Met criteria codes: PM1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.538G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 180 (p.Ala180Thr). This variant has been reported in patients affected with very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and elevated C14:1 and reduced VLCAD activity measured in patient lymphocytes (PP4_Moderate, PMID: 26385305, 31844625, 32778825, 30194637). At least one individual was compound heterozygote with a second ACADVL variant, at least one of these variants is confirmed in trans and approved by the ACADVL VCEP as likely pathogenic (PM3, 1 point, PMID: 31844625, 30194637). The highest population minor allele frequency in gnomAD is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.92, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PM3, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated December 14, 2022 and the recurated classification was approved by the expert panel on April 23, 2023.

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).
• PP4_Moderate: At least one patient with this variant displayed enzyme levels (activity 3% of normal controls) which is highly specific for VLCAD (PP4_moderate) (PMID 30194637). Enriched in VLCADD; 5 alleles (Miller et al.) 4 alleles: heterozygote 1 allele: with p.V283A
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PM3: Seen with p.R456H in Hesse et al. in one patient with 3% residual enzyme activity in lymphocytes, confirmed in trans per personal communication with author. This variant is curated as likely pathogenic by the ACADVL VCEP.

Not Met criteria codes

• PM1: This variant resides within a region of ACADVL that is not defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel. Specifically the variant is located near the enzyme active site (PMID 26385305), but not within the active site.