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]

Variant: NM_000018.4(ACADVL):c.1097G>A (p.Arg366His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA312265

203580 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 05a3bc2c-efbf-4f9f-91c2-b48c53545e2f

Approved on: 2022-09-22

Published on: 2022-09-22

HGVS expressions

NM_000018.4:c.1097G>A

NM_000018.4(ACADVL):c.1097G>A (p.Arg366His)

NC_000017.11:g.7223152G>A

CM000679.2:g.7223152G>A

NC_000017.10:g.7126471G>A

CM000679.1:g.7126471G>A

NC_000017.9:g.7067195G>A

NG_007975.1:g.8319G>A

NG_008391.2:g.1899C>T

ENST00000356839.10:c.1097G>A

ENST00000322910.9:c.*1052G>A

ENST00000350303.9:c.1031G>A

ENST00000356839.9:c.1097G>A

ENST00000543245.6:c.1166G>A

ENST00000578579.2:n.46G>A

ENST00000578824.5:n.513G>A

ENST00000579425.5:n.121G>A

ENST00000582379.1:n.748G>A

ENST00000583858.5:n.126G>A

ENST00000585203.6:n.305G>A

NM_000018.3:c.1097G>A

NM_001033859.2:c.1031G>A

NM_001270447.1:c.1166G>A

NM_001270448.1:c.869G>A

NM_001033859.3:c.1031G>A

NM_001270447.2:c.1166G>A

NM_001270448.2:c.869G>A

Likely Pathogenic

PP3 PP4 PM1 PM3 PM2_Supporting

PM5

Evidence Links 2

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1097G>A (p.Arg366His) variant in ACADVL has been reported in the literature in patients with VLCADD or increased C14:1 acylcarnitine levels (PP4; PMID: 9973285, 20060901, 27246109, 24263034, 32558070). The variant has been detected as homozygote (PMID:24263034), or compound heterozygote with truncating/pathogenic variants, however without phase confirmation (PMID: 32558070, 27246109, 20060901, PM3). The highest population minor allele frequency in gnomAD is 0.0001 in the South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant resides within a region defined as a mutational hotspot by the ClinGen ACADVL Variant Curation Expert Panel (PMID: 9973285, 20060901, PM1). The computational predictor REVEL gives a score of 0.98, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PP4, PM1, PM3, PM2_Supporting, PP3).

PP3

ReVEL score of 0.975

PP4

Reported this variant in heterozygous with R453Ter, with FAO flux of 0.71 (NL 4.8, thus ~15% of NL).

PM1

1. CpG dinucleotides in the codon for arginine326 is a hot spot (PMID: 9973285) 2. Arginine coordinates FAD nucleotide binding. Mutation would be disruptive (PMID: 20060901)

Arginine coordinates FAD nucleotide binding. Mutation would be disruptive. PubMed:20060901

CpG dinucleotides in the codon for arginine326 is a hot spot. PubMed:9973285

PM3

This variant was reported unconfirmed in compound heterozygous with R453Ter with 15% of normal FAO flux (PMID 20060901) and another unconfirmed in compound heterozygous with V283A with abnormal NBS (PMID 27246109). Reported with frameshift mutation in 'patient 3' with VLCADD. Phase not determined.

PM2_Supporting

gnomad has 8 alleles out of 282884 alleles, highest MAF=0.01% in South Asian population; total MAF=0.003%, < 0.1%

PM5

R366C is an alternative change. May classify likely pathogenic with same criteria applied here. In that case it would be PM5_supporting, still not enough to push to R366H to pathogenic.

Curation History

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