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:c.879-8T>A

CA915940901

932828 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4bb34291-25b3-419d-8bef-57a3e7489eb9

HGVS expressions

NM_000018.4:c.879-8T>A

NC_000017.11:g.7222659T>A

CM000679.2:g.7222659T>A

NC_000017.10:g.7125978T>A

CM000679.1:g.7125978T>A

NC_000017.9:g.7066702T>A

NG_007975.1:g.7826T>A

NG_008391.2:g.2392A>T

ENST00000356839.10:c.879-8T>A

ENST00000322910.9:c.*834-8T>A

ENST00000350303.9:c.813-8T>A

ENST00000356839.9:c.879-8T>A

ENST00000543245.6:c.948-8T>A

ENST00000578824.5:n.20T>A

ENST00000581378.5:n.597-8T>A

ENST00000582379.1:n.263-8T>A

NM_000018.3:c.879-8T>A

NM_001033859.2:c.813-8T>A

NM_001270447.1:c.948-8T>A

NM_001270448.1:c.651-8T>A

NM_001033859.3:c.813-8T>A

NM_001270447.2:c.948-8T>A

NM_001270448.2:c.651-8T>A

NM_000018.4(ACADVL):c.879-8T>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4 PP3 PM3 PM2_Supporting PS3_Supporting

PM1 PM4

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.879-8T>A variant in ACADVL is an intronic variant which occurs in intron 9. The variant has been reported twice in the literature in one individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency displaying increased C14:1 acylcarnitine levels, which is highly specific for VLCAD deficiency (PP4; PMID: 19208414; PMID: 20668464). In this same proband, the variant was detected confirmed in-trans with the pathogenic variant c.848T>C (PM3; PMID: 19208414). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.64 for acceptor loss and 0.98 for acceptor gain, predicting that the variant disrupts the acceptor splice site of intron 9 of ACADVL (PP3). RNA sequencing in patient-derived cells demonstrated the presence of alternately spliced transcripts in a proband and the VCEP considered PM4 for an in-frame insertion of two amino acids, but this information is incomplete (PS3_supporting; PMID: 19208414). 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: PP4, PM3, PM2_Supporting, PP3, PS3_Supporting (ACADVL VCEP specifications version 1; approved November 8, 2021).

PP4

Patient has C14:1 acylcarnitine levels >1.0 μM in follow-up plasma acylcarnitine analysis, however no other evidence is provided relating to VLCAD enzyme activity or NBS.

PP3

Both SpliceAI and MaxEntScan predict this change leads to the activation of a cryptic splice acceptor site with an increased exon length of +6 nucleotides (SpliceAI Acceptor Loss delta-score of 0.64 & Acceptor Gain delta-score of 0.98; MaxEntScan at +54.41% variation)

PM3

Detected in-trans with a known pathogenic variant.

PM2_Supporting

Not present in gnomAD

PS3_Supporting

Although RNA sequencing shows evidence of altered splicing, the paper does not specify if there is any remaining evidence of normal splicing. Additionally this patient is compound heterozygous for a non-splicing variant and the result is only a two amino-acid insertion, further complicating the results. Overall, this evidence is downgraded to supporting.

PM1

The position of this insertion is in close proximity to the catalytic center of the M-domain in VLCAD, which is crucial for proper enzyme function. This evidence is incorporated into PM4.

PM4

The activation of a cryptic splice acceptor site leads to a histidine‐to‐glutamine change at amino acid position 293 and introduction of two additional amino acids, histidine and serine, without altering the reading frame increasing the protein length by two.

Approved on: 2023-04-25

Published on: 2023-04-25

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