Variant: NM_000018.4(ACADVL):c.138+1G>A

CA8337554

550796 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: e0c259d4-4bb3-4412-9ad9-2317f6615f83

HGVS expressions

NM_000018.4:c.138+1G>A
NM_000018.4(ACADVL):c.138+1G>A
NC_000017.11:g.7220198G>A
CM000679.2:g.7220198G>A
NC_000017.10:g.7123517G>A
CM000679.1:g.7123517G>A
NC_000017.9:g.7064241G>A
NG_007975.1:g.5365G>A
NG_008391.2:g.4853C>T
ENST00000356839.10:c.138+1G>A
ENST00000322910.9:c.*93+1G>A
ENST00000350303.9:c.138+1G>A
ENST00000356839.9:c.138+1G>A
ENST00000543245.6:c.207+1G>A
ENST00000577191.5:n.215+1G>A
ENST00000577433.5:n.7G>A
ENST00000577857.5:n.228+1G>A
ENST00000578269.5:n.246G>A
ENST00000578421.1:n.272+1G>A
ENST00000579286.5:n.245+1G>A
ENST00000579886.2:c.138+1G>A
ENST00000580263.5:n.228+1G>A
ENST00000581562.5:n.185+1G>A
ENST00000582056.5:n.228+1G>A
ENST00000582356.5:n.263+1G>A
ENST00000583312.5:c.138+1G>A
ENST00000584103.5:c.138+1G>A
NM_000018.3:c.138+1G>A
NM_001033859.2:c.138+1G>A
NM_001270447.1:c.207+1G>A
NM_001270448.1:c.-91+1G>A
NM_001033859.3:c.138+1G>A
NM_001270447.2:c.207+1G>A
NM_001270448.2:c.-91+1G>A

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: BP7 PS1 PP4 PM4 PM5

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specification: ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Evidence submitted by expert panel

ACADVL VCEP

The c.138+1G>A (p.?) (NM_000018.4) variant in ACADVL occurs within the canonical splice acceptor site (+1) of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2/20, 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). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (1/22352 alleles) in SAS population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with this variant in a heterozygous state was positive at NBS or presumed NBS positive; the second allele was not clearly stated (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 11/10/2021).

Met criteria codes

• PVS1: The c.138+1G>A (p.?) (NM_000018.4) variant in ACADVL occurs within the canonical splice acceptor site (+1) of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2/20, 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).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (1/22352 alleles) in SAS population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting).

Not Met criteria codes

• BP7: Variant located at +1 of canonical 5'acceptor splice site.
• PS1: Variant located at +1 of canonical 5'acceptor splice site.
• PP4: At least one patient with this variant in a het state was positive at NBS or presumed NBS positive (PMID: PMID: 26385305). The second allele was not clearly stated.
• PM4: Variant located at +1 of canonical 5'acceptor splice site. Frameshift is predicted.
• PM5: Variant located at +1 of canonical 5'acceptor splice site.

Approved on: 2022-04-06

Published on: 2022-07-12