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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1626 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0e27fe91-6cf2-4326-97b0-f8b2923d9716

Approved on: 2022-01-17

Published on: 2022-09-20

HGVS expressions

NM_000018.4:c.385GAG[1]

NM_000018.4(ACADVL):c.385GAG[1] (p.Glu130del)

Pathogenic

PM2_Supporting PM3_Strong PM4 PS3 PP4

Evidence Links 1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.385GAG[1] variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (p.Glu130del) (PM4). This variant has been detected in at least five individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PMIDs 8554073, 10431122, 27209629,22847164). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those was confirmed in trans by parental testing (PM3_strong, PMID: 10431122). Several patients with this variant displayed VLCADD (PP4, PMIDs 8554073 , 10431122, 27209629, 22847164 ). Assays, including mRNA/protein expression (in CHO cells), and enzymatic activity demonstrate unstable protein products indicating that this variant impacts protein function (PMID: 8554073 )(PS3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic 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: PM4, PM3_strong, PP4, PS3

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PM3_Strong

This variant has been detected in at least five individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PMIDs 8554073, 10431122, 27209629,22847164). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those were confirmed in trans by parental testing (PMID: 10431122 PM3_strong). Points = 0.25 (3) + 0.5 (1) + 1(1)= 2.25 --> PM3_Strong

PM4

In-frame deletion of glutamic acid 130

PS3

Lots of functional studies 8554073 (all abnormal): pulse chase transcript expression protein assembly palmitoyl-CoA dehydrogenase

pulse chase transcript: Unstable protein product. (Figure 6) mRNA expression: 10% of WT. (Table 3) protein assembly from CHO cell: Abnormal based on gel filtration (Figure 7) Reduced palmitoyl-CoA dehydrogenase activity: less than 10% of WT (Table 4) PubMed:8554073

PP4

VLCADD assertion and abnormal acyl carnitine during NBS

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