Variant: NM_000018.4(ACADVL):c.652G>A (p.Glu218Lys)

CA397723393

474901 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 4eb52b3c-3d84-48d6-a3cb-9a64c6d1cb74

Approved on: 2022-12-15

Published on: 2022-12-15

HGVS expressions

NM_000018.4:c.652G>A
NM_000018.4(ACADVL):c.652G>A (p.Glu218Lys)
NC_000017.11:g.7221981G>A
CM000679.2:g.7221981G>A
NC_000017.10:g.7125300G>A
CM000679.1:g.7125300G>A
NC_000017.9:g.7066024G>A
NG_007975.1:g.7148G>A
NG_008391.2:g.3070C>T
ENST00000356839.10:c.652G>A
ENST00000322910.9:c.*607G>A
ENST00000350303.9:c.586G>A
ENST00000356839.9:c.652G>A
ENST00000543245.6:c.721G>A
ENST00000577191.5:n.729G>A
ENST00000577857.5:n.468G>A
ENST00000579286.5:n.833G>A
ENST00000580365.1:n.383G>A
ENST00000581378.5:c.370G>A
ENST00000581562.5:n.554G>A
ENST00000582379.1:n.36G>A
ENST00000583312.5:c.667G>A
ENST00000583760.1:n.434G>A
NM_000018.3:c.652G>A
NM_001033859.2:c.586G>A
NM_001270447.1:c.721G>A
NM_001270448.1:c.424G>A
NM_001033859.3:c.586G>A
NM_001270447.2:c.721G>A
NM_001270448.2:c.424G>A

Uncertain Significance

• Met criteria codes: PM1 PM2_Supporting PP3 PP4

• Not Met criteria codes: PS3

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4(ACADVL):c.652G>A (p.Glu218Lys) variant in ACADVL is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 218 (p.Glu218Lys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000032 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1). This variant was detected in an VLCAD deficiency patient, with reduced enzyme activity, exhibiting reduced ACADVL protein detected by western blot from culture patient fibroblasts (PP4, PMID: 9973285). The computational predictor REVEL gives a score of 0.957, 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 very long chain acyl CoA dehydrogenase (VLCAD) deficiency based on ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, PP3, PP4, PM1.

Met criteria codes

• PM1: This variant resides within a region, amino acids 214–223, of ACADVL that is defined as a mutational hotspot and critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 20060901, 9973285; PM1).
• PM2_Supporting: ). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000032 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.957, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).
• PP4: This variant was detected in an VLCAD deficiency patient, with reduced enzyme activity (PP4).

Not Met criteria codes

• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline