Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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

CA220207

92283 (ClinVar)

Gene: ACADVL (HGNC:37)

Condition: very long chain acyl-CoA dehydrogenase deficiency (MONDO:0008723)

Inheritance Mode: Autosomal recessive inheritance

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

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

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

NM_000018.4:c.425T>C

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

PP4 PP3 PM3_Supporting PM2_Supporting

PS1 PP1 PM4 PM1 PM5 PVS1

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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

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

PM3_Supporting

Described as homozygote in one patient (Table 3). 0.5 point = PM3_supporting

PM2_Supporting

c.425T>C is not found in gnomAD or 1000 Genome projects

PS1

No other codon change seen to cause F142S

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

PVS1

variant is missense, not covered by PVS1

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.