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(ACADVL):c.878+1G>C

CA8337875

941268 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f1d9a549-5b6a-476b-8017-fc9d2f3e4b4c

HGVS expressions

NM_000018.4:c.878+1G>C

NM_000018.4(ACADVL):c.878+1G>C

NC_000017.11:g.7222303G>C

CM000679.2:g.7222303G>C

NC_000017.10:g.7125622G>C

CM000679.1:g.7125622G>C

NC_000017.9:g.7066346G>C

NG_007975.1:g.7470G>C

NG_008391.2:g.2748C>G

ENST00000356839.10:c.878+1G>C

ENST00000322910.9:c.*833+1G>C

ENST00000350303.9:c.812+1G>C

ENST00000356839.9:c.878+1G>C

ENST00000543245.6:c.947+1G>C

ENST00000577191.5:n.1051G>C

ENST00000581378.5:c.596+1G>C

ENST00000582379.1:n.262+1G>C

NM_000018.3:c.878+1G>C

NM_001033859.2:c.812+1G>C

NM_001270447.1:c.947+1G>C

NM_001270448.1:c.650+1G>C

NM_001033859.3:c.812+1G>C

NM_001270447.2:c.947+1G>C

NM_001270448.2:c.650+1G>C

Likely Pathogenic

PM3_Strong PVS1_Moderate PP4_Moderate

PM2

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.878+1G>C variant in ACADVL, also known as IVS9+1G>C, occurs within the canonical splice donor of intron 9. It is predicted to cause skipping of biologically-relevant exon 9/20, resulting in an in-frame deletion (removes amino acids 753-878) that is predicted to escape nonsense mediated decay (PVS1_Moderate). The variant has been described in at least two individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency who displayed increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Moderate; PMIDs: 26927351, 31844625). Each of these affected patients were compound heterozygous for this variant distinct likely pathogenic variants confirmed by parental testing (PM3_Strong; PMIDs: 26927351, 31844625). 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: PVS1_Moderate, PM3_Strong, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).

PM3_Strong

At least two affected patients were compound heterozygous for this variant distinct likely pathogenic variants confirmed by parental testing (PM3_Strong; PMIDs: 26927351, 31844625).

PVS1_Moderate

PP4_Moderate

The variant has been described in at least two individuals, one of whom displayed a newborn screen consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency as well as follow-up acylcarnitine testing showing increased C14:1 acylcarnitines, which is highly specific for VLCAD deficiency (PP4_Moderate; PMIDs: 26927351, 22841441, 31844625).

PM2

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0011 (0.011%) in the East Asian population, which is slightly higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, and thus does not meet this criteria.

Approved on: 2024-02-27

Published on: 2024-02-27

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