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.339C>A (p.Phe113Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA397722617

474895 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 09daa9d6-a08a-4438-8e98-82f288bebeee

Approved on: 2022-12-13

Published on: 2022-12-13

HGVS expressions

NM_000018.4:c.339C>A

NM_000018.4(ACADVL):c.339C>A (p.Phe113Leu)

NC_000017.11:g.7220827C>A

CM000679.2:g.7220827C>A

NC_000017.10:g.7124146C>A

CM000679.1:g.7124146C>A

NC_000017.9:g.7064870C>A

NG_007975.1:g.5994C>A

NG_008391.2:g.4224G>T

ENST00000356839.10:c.339C>A

ENST00000322910.9:c.*294C>A

ENST00000350303.9:c.273C>A

ENST00000356839.9:c.339C>A

ENST00000543245.6:c.408C>A

ENST00000577191.5:n.416C>A

ENST00000577433.5:n.547C>A

ENST00000577857.5:n.290C>A

ENST00000579286.5:n.520C>A

ENST00000579886.2:c.202-118C>A

ENST00000580365.1:n.70C>A

ENST00000581378.5:n.38C>A

ENST00000581562.5:n.386C>A

ENST00000582056.5:n.429C>A

ENST00000582166.1:n.227C>A

ENST00000582356.5:n.538C>A

ENST00000583312.5:c.339C>A

ENST00000584103.5:c.339C>A

NM_000018.3:c.339C>A

NM_001033859.2:c.273C>A

NM_001270447.1:c.408C>A

NM_001270448.1:c.111C>A

NM_001033859.3:c.273C>A

NM_001270447.2:c.408C>A

NM_001270448.2:c.111C>A

Uncertain Significance

PM2_Supporting PM3 PP4_Moderate

PP3 PM1

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.339C>A variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 113 (p.(Phe113Leu)). The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with a distinct pathogenic variant and was confirmed in trans by parental testing (PM3 points = 1.0; PMID: 21932095; c.848T>C, p.(Val243Ala) ClinVar Variation ID: 21025) (PM3). This individual had NBS C14:1 levels (1.10 uM) above the threshold of ≥ 1.0 μM as specified by the ClinGen ACADVL VCEP. Determination of residual VLCAD activity was performed in lymphocytes derived from this individual and these cells retained 22% ACADVL activity (PMID: 21932095) (PP4_Moderate). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722 which is less than the threshold of 0.75 recommended by ClinGen ACADVL VCEP. In summary, this variant meets the criteria to be classified as UNCERTAIN SIGNIFICANCE 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, PM2_Supporting (ClinGen ACADVL VCEP specifications version #1.0; approved 2022-12-13)

PM2_Supporting

PM2_Supporting is met. This variant is absent from gnomAD 2.1.1 (PM2_Supporting).

PM3

PM3 is met. This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was reported as compound heterozygous for the variant and a distinct pathogenic variant and was confirmed in trans by parental testing (PM3 points = 1.0; PMID: 21932095; c.848T>C p.(Val243Ala) ClinVar Variation ID: 21025) (PM3).

PP4_Moderate

PP4_Moderate is met. The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with a distinct pathogenic variant (c.848T>C, p.(Val243Ala) and was confirmed in trans by parental testing (PM3 points = 1.0; PMID: 21932095; c.848T>C p.(Val243Ala) ClinVar Variation ID: 21025) (PM3). NBS C14:1 level = 1.10 umol/L which is above the threshold of 1.0 as specified by ClinGen ACADVL VCEP. Determination of residual VLCAD activity was performed in lymphocytes derived from this individual and these cells retained 22% ACADVL activity (PMID: 21932095) (PP4_Moderate).

PP3

PP3 is not met. The computational predictor REVEL gives a score of 0.722 which is less than the threshold of 0.75 recommended by ClinGen ACADVL VCEP.

PM1

PM1 is not met. Missense variant is not located in ClinGen ACADVL VCEP approved functional domains.

Curation History

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