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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000018.4(ACADVL):c.1141_1143del (p.Glu381del)

CA16041870

371449 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4e2e71ec-b68a-47ac-9f4b-f2d12406bd14

HGVS expressions

NM_000018.4:c.1141_1143del

NM_000018.4(ACADVL):c.1141_1143del (p.Glu381del)

NC_000017.11:g.7223196_7223198del

CM000679.2:g.7223196_7223198del

NC_000017.10:g.7126515_7126517del

CM000679.1:g.7126515_7126517del

NC_000017.9:g.7067239_7067241del

NG_007975.1:g.8363_8365del

NG_008391.2:g.1855_1857del

ENST00000356839.10:c.1141_1143del

ENST00000322910.9:c.*1096_*1098del

ENST00000350303.9:c.1075_1077del

ENST00000356839.9:c.1141_1143del

ENST00000543245.6:c.1210_1212del

ENST00000578579.2:n.90_92del

ENST00000578824.5:n.557_559del

ENST00000579425.5:n.165_167del

ENST00000582379.1:n.792_794del

ENST00000583858.5:n.170_172del

ENST00000585203.6:n.349_351del

NM_000018.3:c.1141_1143del

NM_001033859.2:c.1075_1077del

NM_001270447.1:c.1210_1212del

NM_001270448.1:c.913_915del

NM_001033859.3:c.1075_1077del

NM_001270447.2:c.1210_1212del

NM_001270448.2:c.913_915del

Pathogenic

PP4_Moderate PM2_Supporting PM1 PM4 PM3_Strong

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1141_1143delGAG 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.Glu381del) (PM4). The variant is reported in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency (PMID: 25834949, 24305961, 21814341, 8845838). Six individuals were reported to have both elevated C14:1 levels and reduced VLCAD enzyme activity, which is highly specific for VLCAD deficiency (PP4_moderate; PMIDs: 8845838, 21814341, 24305961, 25834949, 31031081). Of these individuals, one individual was homozygous for this variant, at least two of the individuals also carried an additional pathogenic variant not confirmed in trans, and at least four confirmed in trans to variants not yet curated by the VCEP (PM3; PMID: 24305961, 25834949, 32276429). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within a region of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM1, PM2_supporting, PM3, PM4, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021).

PP4_Moderate

There are many probands with both elevated C14:1 levels and reduced VLCAD enzyme activity individually, as well as a couple with both at once. This previously met Strong, however due to specification revisions is reduced to Moderate.

PM2_Supporting

Not in gnomAD or ExAC

PM1

Both R366H and K382Q, the latter of which is next to this deletion, cause weakened FAD binding and decreased association between enzyme monomers via salt bridge interaction. Therefore, since this variant occurs in a well-established functional domain, this meets PM1.

PM4

This indel (p.Glu381del) leads to a shortened protein in a non-repeat region, and therefore meets PM4.

PM3_Strong

Seen not confirmed in-trans with known pathogenic variant Val283Ala in at least two individuals (provisional pathogenic). However, also seen in homozygous state.

Approved on: 2022-08-09

Published on: 2022-08-09

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