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.1269+1G>A

CA8338049

555644 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b2626b0a-2155-4590-95f7-6bddd75d6b27

HGVS expressions

NM_000018.4:c.1269+1G>A

NM_000018.4(ACADVL):c.1269+1G>A

NC_000017.11:g.7223731G>A

CM000679.2:g.7223731G>A

NC_000017.10:g.7127050G>A

CM000679.1:g.7127050G>A

NC_000017.9:g.7067774G>A

NG_007975.1:g.8898G>A

NG_008391.2:g.1320C>T

NG_033038.1:g.15814C>T

ENST00000356839.10:c.1269+1G>A

ENST00000322910.9:c.*1224+1G>A

ENST00000350303.9:c.1203+1G>A

ENST00000356839.9:c.1269+1G>A

ENST00000542255.6:n.127+1G>A

ENST00000543245.6:c.1338+1G>A

ENST00000578579.2:n.440+1G>A

ENST00000578711.1:n.227G>A

ENST00000578824.5:n.685+1G>A

ENST00000579425.5:n.293+1G>A

ENST00000579546.1:n.106+1G>A

ENST00000583850.5:n.44+1G>A

ENST00000583858.5:n.298+1G>A

ENST00000585203.6:n.477+1G>A

NM_000018.3:c.1269+1G>A

NM_001033859.2:c.1203+1G>A

NM_001270447.1:c.1338+1G>A

NM_001270448.1:c.1041+1G>A

NM_001033859.3:c.1203+1G>A

NM_001270447.2:c.1338+1G>A

NM_001270448.2:c.1041+1G>A

Likely Pathogenic

PVS1_Moderate PM3_Supporting PM2_Supporting PP4_Moderate

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1269+1G>A variant in ACADVL, also published as IVS12+1G>A, occurs within the canonical splice donor site (+/- 1,2) of intron 12. It is predicted to cause skipping of biologically-relevant-exon 12/20, resulting in an in-frame deletion (removes amino acids 395-423) that is predicted to escape nonsense mediated decay (PVS1_Moderate). This variant has been described without an additional ACADVL variant in 3 individuals identified by newborn screen, identified in an unknown phase to a variant of uncertain significance in two individuals, and has also been identified occurring in the homozygous state in an individual identified by newborn screen (PM3_Supporting, PMIDs: 32793418, 30194637, 25834949, 21932095, 21531094). The individual who carried the c.1269+1G>A variant in the homozygous state also displayed reduced VLCAD enzyme activity, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMID: 25834949). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the 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 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_Supporting, PP4_Moderate, PM2_Supporting (VCEP specifications version 1; approved November 8, 2021)

PVS1_Moderate

The c.1269+1G>A variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 12. It is predicted to cause skipping of biologically-relevant-exon 12/20, resulting in an in-frame deletion (removes amino acids 395-423) that is predicted to escape nonsense mediated decay (PVS1_Moderate).

PM3_Supporting

Patient 2 in PMID 25834949 is homozygous for the variant.

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the 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).

PP4_Moderate

Patient 2 in PMID 25834949 identified by abnormal newborn screen, homozygous for the variant, displayed reduced VLCAD activity and LC-FAO-flux

Approved on: 2022-12-14

Published on: 2022-12-14

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.