Variant: NM_000018.4(ACADVL):c.1077+1G>T

CA16041867

370482 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: dbfa454a-78d2-4c11-b4a1-d91bb22dc523

HGVS expressions

NM_000018.4:c.1077+1G>T
NM_000018.4(ACADVL):c.1077+1G>T
NC_000017.11:g.7222866G>T
CM000679.2:g.7222866G>T
NC_000017.10:g.7126185G>T
CM000679.1:g.7126185G>T
NC_000017.9:g.7066909G>T
NG_007975.1:g.8033G>T
NG_008391.2:g.2185C>A
ENST00000356839.10:c.1077+1G>T
ENST00000322910.9:c.*1032+1G>T
ENST00000350303.9:c.1011+1G>T
ENST00000356839.9:c.1077+1G>T
ENST00000543245.6:c.1146+1G>T
ENST00000578824.5:n.227G>T
ENST00000582379.1:n.462G>T
ENST00000583858.5:n.106+1G>T
ENST00000585203.6:n.19G>T
NM_000018.3:c.1077+1G>T
NM_001033859.2:c.1011+1G>T
NM_001270447.1:c.1146+1G>T
NM_001270448.1:c.849+1G>T
NM_001033859.3:c.1011+1G>T
NM_001270447.2:c.1146+1G>T
NM_001270448.2:c.849+1G>T

Likely Pathogenic

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

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: PP4

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1077+1G>T variant in ACADVL is a splice site variant affecting the canonical donor splice site in intron 10. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present at low frequency (1 allele, <0.1%) in large population database (PM2_supporting, gnomad). This variant has been reported in abnormal newborn screen with 36% residual enzyme activity (PP4 not met) without clinical confirmation or a second variant identified (PMID 21932095). In summary, this variant meets criteria to be classified as likely pathogenic for VLCAD in an AR manner. ACADVL-specific ACMG/AMP criteria applied: PVS1, PM2_supporting.

Met criteria codes

• PVS1: c.1077+1G>T affects canonical donor splice site in intron 10 which is predicted to disrupt splicing causing the skipping of exon 10, which would lead to frameshift, premature stop codon, and NMD.
• PM2_Supporting: 1 allele observed (<0.1%) in population database (gnomad)

Not Met criteria codes

• PP4: Clinical information and confirmatory study not provided. A second potential disease causing variant not identified. 36% residual enzyme does not meet PP4.

Approved on: 2022-09-22

Published on: 2022-09-22