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.1077+2T>C

CA16041868

370279 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 18d16659-a3cd-447e-a2ce-81118ba28fdf

HGVS expressions

NM_000018.4:c.1077+2T>C

NM_000018.4(ACADVL):c.1077+2T>C

NC_000017.11:g.7222867T>C

CM000679.2:g.7222867T>C

NC_000017.10:g.7126186T>C

CM000679.1:g.7126186T>C

NC_000017.9:g.7066910T>C

NG_007975.1:g.8034T>C

NG_008391.2:g.2184A>G

ENST00000356839.10:c.1077+2T>C

ENST00000322910.9:c.*1032+2T>C

ENST00000350303.9:c.1011+2T>C

ENST00000356839.9:c.1077+2T>C

ENST00000543245.6:c.1146+2T>C

ENST00000578824.5:n.228T>C

ENST00000582379.1:n.463T>C

ENST00000583858.5:n.106+2T>C

ENST00000585203.6:n.20T>C

NM_000018.3:c.1077+2T>C

NM_001033859.2:c.1011+2T>C

NM_001270447.1:c.1146+2T>C

NM_001270448.1:c.849+2T>C

NM_001033859.3:c.1011+2T>C

NM_001270447.2:c.1146+2T>C

NM_001270448.2:c.849+2T>C

Pathogenic

PM2_Supporting PVS1 PM3_Supporting PP4_Moderate

PS3

Evidence Links 1

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4:c.1077+2T>C variant in ACADVL occurs within the canonical splice donor site (+/- 1,2) of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10/20, 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 three homozygous siblings with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who inherited the variant from heterozygous parents (PMID:25338548)(PM3_Supporting, points=0.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two patients with this variant displayed elevated C14:1 levels ≥ 1.0 μM and VLCAD enzyme activity <20% of control in proband fibroblast (PMID:25338548, 9973285), which is highly specific for VLCADD (PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on PVS1,PM2_supporting,PM3_Supporting, PP4_Moderate.

PM2_Supporting

This variant is absent in gnomAD, meeting PM2.

PVS1

c.1077+2T>C affects canonical donor splice site in intron 10 which is predicted to disrupt splicing causing the skipping of exon 10, which would lead to frameshift, PTC, and NMD.

PM3_Supporting

Reported this variant as homozygous in a family of 3 affected children and both parents are heterozygous carriers. PM3 points = 0.5

PP4_Moderate

C14:1 in two of the three affected siblings are 3.6, 1.38 (ref <0.19), thus meet PP4_moderate. Index patient VLCAD in Fibroblast 0.1 (ref 3.4+-0.9), <20% of control.

PS3

The second variant was not identified in this patient. Although the protein was shown to be decreased in patient's fibroblasts; however, mRNA not analyzed.

This variant was reported in Table 2 as +2T>C in 1 patient without a second variant mentioned. The protein was shown to be decreased in patient's fibroblasts; however, mRNA not analyzed. Per methdology, all patients in the study with index case experiencing clinical symptoms with enzyme defects in cultured skin fibroblasts; however, values not given thus PP4 not met. Per methdology, mutant variants were cloned from patient fibroblast into a vector and sequenced; wild type, mutant and vector alone were transfected into COS-7 cells, but results were not shown. PS3 not met PubMed:9973285

Approved on: 2022-09-29

Published on: 2022-09-29

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