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]

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Variant: NM_000018.4(ACADVL):c.194C>T (p.Pro65Leu)

CA285292

38798 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fc9045f6-6b42-44b3-91a2-bb334c06b05f

Approved on: 2022-03-08

Published on: 2022-03-08

HGVS expressions

NM_000018.4:c.194C>T

NM_000018.4(ACADVL):c.194C>T (p.Pro65Leu)

NC_000017.11:g.7220519C>T

CM000679.2:g.7220519C>T

NC_000017.10:g.7123838C>T

CM000679.1:g.7123838C>T

NC_000017.9:g.7064562C>T

NG_007975.1:g.5686C>T

NG_008391.2:g.4532G>A

ENST00000356839.10:c.194C>T

ENST00000322910.9:c.*149C>T

ENST00000350303.9:c.139-85C>T

ENST00000356839.9:c.194C>T

ENST00000543245.6:c.263C>T

ENST00000577191.5:n.271C>T

ENST00000577433.5:n.328C>T

ENST00000577857.5:n.229-247C>T

ENST00000578269.5:n.567C>T

ENST00000578421.1:n.328C>T

ENST00000579286.5:n.301C>T

ENST00000579886.2:c.194C>T

ENST00000580263.5:n.284C>T

ENST00000581562.5:n.241C>T

ENST00000582056.5:n.284C>T

ENST00000582166.1:n.82C>T

ENST00000582356.5:n.319C>T

ENST00000583312.5:c.194C>T

ENST00000584103.5:c.194C>T

NM_000018.3:c.194C>T

NM_001033859.2:c.139-85C>T

NM_001270447.1:c.263C>T

NM_001270448.1:c.-35C>T

NM_001033859.3:c.139-85C>T

NM_001270447.2:c.263C>T

NM_001270448.2:c.-35C>T

Benign

BA1 BS3_Supporting BP4

BP2 PS3

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.194C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 65 (p.Pro65Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1129 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). Palmitoyl-CoA dehydrogenase activity in VLCAD-null fibroblasts transfected with c.194C>T cDNA showed activity comparable to the cells transfected with wild-type cDNA indicating that this variant does not impact protein function (PMID: 10790204, BS3_supporting). The computational predictor REVEL gives a score of 0.276, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign 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: BA1, BS3_supporting, BP4 (VCEP specifications v2.0, approved on 09/16/2021).

BA1

MAF of 0.1129 in the African Population in gnomAD

BS3_Supporting

Two mutant cDNAs having either K247Q or P65L were transiently expressed in SV40-transformed fibroblasts from a patient with homozygous null variants. Palmitoyl-CoA dehydrogenase activity in the transfectants with normal VLCAD was more than 15 times higher than the endogenous activity with mock cDNAs, and the activity in the transfectant with P65L was almost the same as that with normal cDNA. Ths is a generally accepted assay and so meets BS3 supporting.

BP4

REVEL score of 0.276

BP2

Observed in-cis with 739A>C (K247Q), a known pathogenic variant; however, the VCEP has not yet curated this variant.

PS3

Although there is some evidence that this variant causes abberant splicing, other follow-up sources such as PMID:17374501 demonstrated that this still results in a stable protein that has a high specific activity. Therefore, this does not meet PS3.

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