Variant: NM_000018.4(ACADVL):c.753-2A>C

CA220220

92290 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 6aa11fe3-6074-41da-ad5f-54746213c564

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

NM_000018.4:c.753-2A>C
NM_000018.4(ACADVL):c.753-2A>C
NC_000017.11:g.7222175A>C
CM000679.2:g.7222175A>C
NC_000017.10:g.7125494A>C
CM000679.1:g.7125494A>C
NC_000017.9:g.7066218A>C
NG_007975.1:g.7342A>C
NG_008391.2:g.2876T>G
ENST00000356839.10:c.753-2A>C
ENST00000322910.9:c.*708-2A>C
ENST00000350303.9:c.687-2A>C
ENST00000356839.9:c.753-2A>C
ENST00000543245.6:c.822-2A>C
ENST00000577191.5:n.923A>C
ENST00000581378.5:c.471-2A>C
ENST00000582379.1:n.137-2A>C
NM_000018.3:c.753-2A>C
NM_001033859.2:c.687-2A>C
NM_001270447.1:c.822-2A>C
NM_001270448.1:c.525-2A>C
NM_001033859.3:c.687-2A>C
NM_001270447.2:c.822-2A>C
NM_001270448.2:c.525-2A>C

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP4_Moderate

• Not Met criteria codes: PM3

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.753-2A>C variant in ACADVL occurs within the canonical splice acceptor site (+/- 1,2) of intron 8. It is predicted to cause skipping of biologically-relevant-exon 9/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 9973285, 11590124). This variant has been identified by positive newborn screen in several individuals and in individuals presenting with very long-chain acyl-CoA dehydrogenase deficiency (PMID 27246109, 26385305, 21378393, 17999356, 16488171, 10738914, 10077518, 9973285). This variant is reported in two individuals with a beta-oxidation flux less than 20% of normal (PM2_Supporting, PMID: 21378393, 17999356). In at least one individual, an additional likely pathogenic variant was identified, though the phase of these variants was unknown (PMID: 16488171). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic 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: PVS1, PM2_Supporting, PP4_Moderate (VCEP specifications v2.0, approved on 09/16/2021).

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion.
• PVS1: The c.753-2A>C variant in ACADVL occurs within the canonical splice acceptor site (+/- 1,2) of intron 8. It is predicted to cause skipping of biologically-relevant-exon 9/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID 9973285, 11590124).
• PP4_Moderate: This variant has been identified by positive newborn screen in several individuals and in individuals presenting with very long-chain acyl-CoA dehydrogenase deficiency (PMID 27246109, 26385305, 21378393, 17999356, 16488171, 10738914, 10077518, 9973285). This variant is reported in two individuals with a beta-oxidation flux less than 20% of normal (PMID: 21378393, 17999356).

Not Met criteria codes

• PM3: Although this variant has been identified in individuals with very long-chain acyl-CoA dehydrogenase deficiency and an additional pathogenic variant, none of these variants were confirmed to be in trans to c.753-2A>C (PMID: 16488171, 27246109).