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.1066A>G (p.Ile356Val)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA200650

193541 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 61e40fb3-21f4-43ac-af6c-3116fb9fcaf6

Approved on: 2024-12-10

Published on: 2024-12-10

HGVS expressions

NM_000018.4:c.1066A>G

NM_000018.4(ACADVL):c.1066A>G (p.Ile356Val)

NC_000017.11:g.7222854A>G

CM000679.2:g.7222854A>G

NC_000017.10:g.7126173A>G

CM000679.1:g.7126173A>G

NC_000017.9:g.7066897A>G

NG_007975.1:g.8021A>G

NG_008391.2:g.2197T>C

ENST00000356839.10:c.1066A>G

ENST00000322910.9:c.*1021A>G

ENST00000350303.9:c.1000A>G

ENST00000356839.9:c.1066A>G

ENST00000543245.6:c.1135A>G

ENST00000578824.5:n.215A>G

ENST00000582379.1:n.450A>G

ENST00000583858.5:c.95A>G

ENST00000585203.6:n.7A>G

NM_000018.3:c.1066A>G

NM_001033859.2:c.1000A>G

NM_001270447.1:c.1135A>G

NM_001270448.1:c.838A>G

NM_001033859.3:c.1000A>G

NM_001270447.2:c.1135A>G

NM_001270448.2:c.838A>G

Uncertain Significance

PP4 BA1

PP3 PM1 PM5 PM3_Supporting BP4

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1066A>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 356 (p.Ile356Val). Several individuals with this variant were identified by newborn screen, but this information is insufficient to use toward classification (PMID: 30194637, 26385305, 23867825, 31031081, 27209629). One individual did display C14:1 level of 0.83, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4, PMID: 31031081). At least one of these individuals carried an additional likely pathogenic variant not confirmed to be in trans, but this does not meet the criteria to be counted toward PM3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.009786 in the African population with 3 total homozygotes, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). However, due to the possibility of this variant being enriched in an under-sequenced population, the ACADVL VCEP has overridden the BA1 evidence code to be in conflict with the specificity of the C14:1 level identified in an affected individual (PP4 data, PMID: 31031081). Additionally, the ACADVL VCEP cannot exclude the possibility that the 3 homozygous individuals in gnomAD may be as-yet unaffected adults that could present with mild disease in the future. The computational predictor REVEL gives a score of 0.621, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. In summary, this variant meets the criteria to be classified as variant of 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: BA1, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on December 10, 2025.

PP4

The majority of probands observed with this variant have abnormal newborn screening (highest value C14:1 of 0.83), however the only value for VLCAD enzyme activity was in a carrier (38% residual activity in lymphocytes).

BA1

Allele frequency is 0.009786 with 3 homozygotes in the African population, >0.7%

PP3

REVEL score of 0.621

PM1

Although the variant could lead to a less stable protein, partial functionality plus the lack of any critical domains does not meet this criteria

PM5

Only amino acid change observed has not been published

PM3_Supporting

This variant has been observed not confirmed in-trans with two variants, one pathogenic and one likely pathogenic. Only one likely pathogenic proband has enough data to be counted for PP4 (PMID: 31031081, Proband 14) but 0.25 points fails to meet the criteria.

BP4

REVEL score of 0.621

Curation History

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