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.277+2T>G

CA397722484

556238 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b16ab476-ad69-4027-a8a9-0d107b58db50

Approved on: 2022-03-08

Published on: 2022-04-06

HGVS expressions

NM_000018.4:c.277+2T>G

NM_000018.4(ACADVL):c.277+2T>G

NC_000017.11:g.7220678T>G

CM000679.2:g.7220678T>G

NC_000017.10:g.7123997T>G

CM000679.1:g.7123997T>G

NC_000017.9:g.7064721T>G

NG_007975.1:g.5845T>G

NG_008391.2:g.4373A>C

ENST00000356839.10:c.277+2T>G

ENST00000322910.9:c.*232+2T>G

ENST00000350303.9:c.211+2T>G

ENST00000356839.9:c.277+2T>G

ENST00000543245.6:c.346+2T>G

ENST00000577191.5:n.354+2T>G

ENST00000577433.5:n.485+2T>G

ENST00000577857.5:n.229-88T>G

ENST00000578421.1:n.487T>G

ENST00000579286.5:n.458+2T>G

ENST00000579886.2:c.201+152T>G

ENST00000580263.5:n.443T>G

ENST00000581562.5:n.324+2T>G

ENST00000582056.5:n.367+2T>G

ENST00000582166.1:n.165+2T>G

ENST00000582356.5:n.476+2T>G

ENST00000583312.5:c.277+2T>G

ENST00000584103.5:c.277+2T>G

NM_000018.3:c.277+2T>G

NM_001033859.2:c.211+2T>G

NM_001270447.1:c.346+2T>G

NM_001270448.1:c.49+2T>G

NM_001033859.3:c.211+2T>G

NM_001270447.2:c.346+2T>G

NM_001270448.2:c.49+2T>G

Pathogenic

PM2_Supporting PVS1 PM3

PP4 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.277+2T>G variant in ACADVL occurs within the canonical splice donor (+2) of intron 4. It is predicted to cause skipping of biologically-relevant-exon 4/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a distinct pathogenic or likely pathogenic variant; confirmed in trans by parental testing (c.388_390del; VCV000001626.12; PM3 points = 1.0, PMID:22847164) (PM3). To our knowledge, functional assays have not been reported for this variant. PM2_Supporting is met. This variant is absent from gnomAD v2.1.1 (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: PVS1, PM3, PM2_Supporting; VCEP specifications v2.0; approved 12-09-21.

PM2_Supporting

PM2_Supporting is met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PVS1

PVS1 is met. The c.277+2T>G variant in ACADVL occurs within the canonical splice donor (+2) of intron 4. It is predicted to cause skipping of biologically-relevant-exon 4/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124).

PM3

PM3 is met. This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant was confirmed in trans by parental testing (c.388_390del; VCV000001626.12; PM3 points = 1.0, PMID:22847164) (PM3).

PP4

PP4 is not met. Individual was not identified through a NBS program. Elevated plasma C14:1-carnitine elevated to 0.57 µmol/L (RI <0.34).

PM4

PM4 is not met. Variant at canonical 5' donor splice site predicted to result in skipping of exon 4 which leads to frameshift.

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