Variant: NM_000018.4(ACADVL):c.425T>C (p.Phe142Ser)

CA220207

92283 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 3f32f6a5-2276-4bab-b736-853284e9704f

HGVS expressions

NM_000018.4:c.425T>C
NM_000018.4(ACADVL):c.425T>C (p.Phe142Ser)
NC_000017.11:g.7221006T>C
CM000679.2:g.7221006T>C
NC_000017.10:g.7124325T>C
CM000679.1:g.7124325T>C
NC_000017.9:g.7065049T>C
NG_007975.1:g.6173T>C
NG_008391.2:g.4045A>G
ENST00000356839.10:c.425T>C
ENST00000322910.9:c.*380T>C
ENST00000350303.9:c.359T>C
ENST00000356839.9:c.425T>C
ENST00000543245.6:c.494T>C
ENST00000577191.5:n.502T>C
ENST00000577433.5:n.633T>C
ENST00000577857.5:n.293+176T>C
ENST00000579286.5:n.606T>C
ENST00000579886.2:c.263T>C
ENST00000580365.1:n.156T>C
ENST00000581378.5:n.124T>C
ENST00000581562.5:n.472T>C
ENST00000582056.5:n.608T>C
ENST00000582166.1:n.406T>C
ENST00000583312.5:c.425T>C
ENST00000584103.5:c.458T>C
NM_000018.3:c.425T>C
NM_001033859.2:c.359T>C
NM_001270447.1:c.494T>C
NM_001270448.1:c.197T>C
NM_001033859.3:c.359T>C
NM_001270447.2:c.494T>C
NM_001270448.2:c.197T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting PM3_Supporting PP4 PP3

• Not Met criteria codes: PVS1 PP1 PM4 PM1 PM5 PS1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.425T>C variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 142 (p.Phe142Ser). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94, which is above the threshold 0.75, evidence that correlates with impact to ACADVL function (PP3). At least one patient with this variant displayed organic acidemia and fatty acid oxidation issues, which are highly specific for VLCAD deficiency (PP4, PMID: 27629047, PMID: 28980192). This individual was also reported homozygous for the variant (PMID: 27629047; points=0.5; PM3_supporting). In summary, this variant meets the criteria to be classified as VUS 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: PM2,PM3_supporting PP3, PP4

Met criteria codes

• PM2_Supporting: c.425T>C is not found in gnomAD or 1000 Genome projects
• PM3_Supporting: Described as homozygote in one patient (Table 3). 0.5 point = PM3_supporting
• PP4: One proband case was found (Saudi Arabia) and diagnosed with VLCAD deficiency. Only a phenotypic description was given - no enzyme level or acylcarnitine analysis data.
• PP3: REVEL score is 0.944 which passes the ACADVL criteria of greater than 0.75

Not Met criteria codes

• PVS1: variant is missense, not covered by PVS1
• PP1: No segregation data found
• PM4: Phe142Ser does not alter protein length
• PM1: Phe142 is not located in a designated hotspot or functional domain
• PM5: No other missense change seen at this residue
• PS1: No other codon change seen to cause F142S

Approved on: 2022-12-14

Published on: 2022-12-14