Variant: NM_000018.4(ACADVL):c.1532+2T>C

CA16041875

370770 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: ec8e1da9-9978-4bde-a32e-07cdbc115cd7

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

NM_000018.4:c.1532+2T>C
NM_000018.4(ACADVL):c.1532+2T>C
NC_000017.11:g.7224245T>C
CM000679.2:g.7224245T>C
NC_000017.10:g.7127564T>C
CM000679.1:g.7127564T>C
NC_000017.9:g.7068288T>C
NG_007975.1:g.9412T>C
NG_008391.2:g.806A>G
NG_033038.1:g.15300A>G
ENST00000356839.10:c.1532+2T>C
ENST00000322910.9:c.*1487+2T>C
ENST00000350303.9:c.1466+2T>C
ENST00000356839.9:c.1532+2T>C
ENST00000542255.6:n.390+2T>C
ENST00000543245.6:c.1601+2T>C
ENST00000578319.5:n.27+2T>C
ENST00000578711.1:n.741T>C
ENST00000578809.5:n.29T>C
ENST00000579391.1:n.140+2T>C
ENST00000579425.5:n.648+2T>C
ENST00000579546.1:n.272-76T>C
ENST00000579894.5:n.319+2T>C
ENST00000583074.5:n.154-76T>C
ENST00000583850.5:n.307+2T>C
ENST00000583858.5:n.464-76T>C
ENST00000585203.6:n.723+2T>C
NM_000018.3:c.1532+2T>C
NM_001033859.2:c.1466+2T>C
NM_001270447.1:c.1601+2T>C
NM_001270448.1:c.1304+2T>C
NM_001033859.3:c.1466+2T>C
NM_001270447.2:c.1601+2T>C
NM_001270448.2:c.1304+2T>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PM2_Supporting PVS1

• Not Met criteria codes: PP4

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1532+2T>C variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 15. It is predicted to cause skipping of biologically-relevant-exon 15/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1 is 0.00005440 in the East Asian 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 likely 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. (ACADVL VCEP specifications version 1; approved November 8, 2021)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1 is 0.00005440 in the East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PVS1: The c.1532+2T>C variant in ACADVL occurs within the canonical splice donor/acceptor site (+/- 1,2) of intron 15. It is predicted to cause skipping of biologically-relevant-exon 15/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124).

Not Met criteria codes

• PP4: At least one individual with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305).