NM_000018.4:c.1500_1502del

CA8338130

854401 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 80503468-04e2-4bf8-a9e2-1d0eb506af0c

Approved on: 2022-12-13

Published on: 2022-12-13

HGVS expressions

NM_000018.4:c.1500_1502del
NM_000018.4:c.1497CCT[1]
NC_000017.11:g.7224211_7224213del
CM000679.2:g.7224211_7224213del
NC_000017.10:g.7127530_7127532del
CM000679.1:g.7127530_7127532del
NC_000017.9:g.7068254_7068256del
NG_007975.1:g.9378_9380del
NG_008391.2:g.841_843del
NG_033038.1:g.15335_15337del
ENST00000356839.10:c.1500_1502del
ENST00000322910.9:c.*1455_*1457del
ENST00000350303.9:c.1434_1436del
ENST00000356839.9:c.1500_1502del
ENST00000542255.6:n.358_360del
ENST00000543245.6:c.1569_1571del
ENST00000578711.1:n.707_709del
ENST00000579391.1:n.108_110del
ENST00000579425.5:n.616_618del
ENST00000579546.1:n.272-110_272-108del
ENST00000579894.5:n.287_289del
ENST00000583074.5:n.154-110_154-108del
ENST00000583850.5:n.275_277del
ENST00000583858.5:n.464-110_464-108del
ENST00000585203.6:n.691_693del
NM_000018.3:c.1500_1502del
NM_001033859.2:c.1434_1436del
NM_001270447.1:c.1569_1571del
NM_001270448.1:c.1272_1274del
NM_001033859.3:c.1434_1436del
NM_001270447.2:c.1569_1571del
NM_001270448.2:c.1272_1274del
NM_000018.4(ACADVL):c.1497CCT[1] (p.Leu502del)

Likely Pathogenic

• Met criteria codes: PP1_Moderate PP4_Moderate PM2_Supporting PM3 PM1 PM4

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.1500_1502del variant is predicted to cause a change in the length of the protein (p.Leu502del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4). This variant has been detected in six individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, one was assumed compound heterozygous for the variant and a distinct pathogenic variant, p.Val243Ala; parental confirmation was not provided (PM3 points=0.5, PMID: 30194637, ClinVar Variation ID: 21025). Five individuals were homozygous for the variant (PM3 points = 1.0 max, PMIDs: 26385305, 27943070, 24765510, 32793418) (Total PM3 points = 1.5; PM3). At least one patient with this variant displayed VLCAD enzyme activity <= 20% of normal which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMIDs: 30194637, 27943070, 32793418). This variant resides within a region, amino acids 481-516: Membrane binding, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 18227065, 20060901) (PM1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008795 in 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 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: PM3, PP4_Moderate, PM1, PM4, PM2_Supporting. (ClinGen ACADVL VCEP specifications version#1.0; approved 12-13-22)

Met criteria codes

• PP1_Moderate: PP1_Moderate is met.
• PP4_Moderate: PP4_Moderate is met. At least one patient with this variant displayed VLCAD enzyme activity <= 20% of normal which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMIDs: 30194637, 27943070, 32793418).
• PM2_Supporting: PM2_Supporting is met. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008795 in 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).
• PM3: PM3 is met. This variant has been detected in six individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, one was assumed compound heterozygous for the variant and a distinct pathogenic variant, p.Val243Ala; parental confirmation was not provided (PM3 points=0.5, PMID: 30194637, ClinVar Variation ID: 21025). Five individuals were homozygous for the variant (PM3 points = 1.0 max, PMIDs: 26385305, 27943070, 24765510, 32793418) (Total PM3 points = 1.5; PM3).
• PM1: PM1 is met. This variant resides within a region, amino acids 481-516: Membrane binding, of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PMIDs: 18227065, 20060901) (PM1).
• PM4: PM4 is met. The c.1500_1502del variant is predicted to cause a change in the length of the protein (p.Leu502del) due to an in-frame deletion of one amino acid in a non-repeat region (PM4).