Variant: NM_000018.4(ACADVL):c.1748C>T (p.Ser583Leu)

CA397725788

550315 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: daa2980e-2f60-4a41-89a4-e564f6ab02ce

HGVS expressions

NM_000018.4:c.1748C>T
NM_000018.4(ACADVL):c.1748C>T (p.Ser583Leu)
NC_000017.11:g.7224711C>T
CM000679.2:g.7224711C>T
NC_000017.10:g.7128030C>T
CM000679.1:g.7128030C>T
NC_000017.9:g.7068754C>T
NG_007975.1:g.9878C>T
NG_008391.2:g.340G>A
NG_033038.1:g.14834G>A
ENST00000356839.10:c.1748C>T
ENST00000322910.9:c.*1703C>T
ENST00000350303.9:c.1682C>T
ENST00000356839.9:c.1748C>T
ENST00000542255.6:n.537-4C>T
ENST00000543245.6:c.1817C>T
ENST00000578033.1:n.79C>T
ENST00000578319.5:n.329C>T
ENST00000578711.1:n.1207C>T
ENST00000578809.5:n.320C>T
ENST00000579425.5:n.864C>T
ENST00000579546.1:n.483C>T
ENST00000583074.5:n.300-4C>T
ENST00000583848.5:n.114C>T
ENST00000583850.5:n.519C>T
ENST00000583858.5:n.679C>T
ENST00000585203.6:n.939C>T
NM_000018.3:c.1748C>T
NM_001033859.2:c.1682C>T
NM_001270447.1:c.1817C>T
NM_001270448.1:c.1520C>T
NM_001033859.3:c.1682C>T
NM_001270447.2:c.1817C>T
NM_001270448.2:c.1520C>T

Uncertain Significance

• Met criteria codes: PP4 PM2_Supporting PM3

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4(ACADVL): c.1748C>T (p.Ser583Leu) variant in ACADVL is a missense variant predicted to cause substitution of serine by leucine at amino acid 583 (p.Ser583Leu). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, both were homozygous for the variant; Moreover, this variant was co-detected with c.848T>C (p.Val283Ala) variant with unknown phase (PM3 point 1.5, PMIDs 32518924, 23774949) (PM3). At least two patients with this variant in homozygous state displayed clinical phonotypes, NBS abnormalities and/or increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Supporting, PMIDs 32518924). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305).The highest population minor allele frequency in gnomAD v2.1.1 is 0.000034 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). The computational predictor REVEL gives a score of 0.674, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. 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 the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PM2_Supporting, PP4_Supporting.

Met criteria codes

• PP4: At least two patients with this variant in homozygous state displayed clinical phonotypes, NGS abnormalities and/or increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Supporting, PMIDs 32518924).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.000034 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).
• PM3: Of those individuals, both were homozygous for the variant (PM3 point 1.0, PMID 32518924) (PM3).

Approved on: 2022-12-15

Published on: 2022-12-15