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.577G>C (p.Gly193Arg)

CA8337761

932788 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f33d8613-7ef9-4f85-aca2-93e6e59138d7

HGVS expressions

NM_000018.4:c.577G>C

NM_000018.4(ACADVL):c.577G>C (p.Gly193Arg)

NC_000017.11:g.7221637G>C

CM000679.2:g.7221637G>C

NC_000017.10:g.7124956G>C

CM000679.1:g.7124956G>C

NC_000017.9:g.7065680G>C

NG_007975.1:g.6804G>C

NG_008391.2:g.3414C>G

ENST00000356839.10:c.577G>C

ENST00000322910.9:c.*532G>C

ENST00000350303.9:c.511G>C

ENST00000356839.9:c.577G>C

ENST00000543245.6:c.646G>C

ENST00000577191.5:n.654G>C

ENST00000577433.5:n.785G>C

ENST00000577857.5:n.393G>C

ENST00000579286.5:n.758G>C

ENST00000579886.2:c.415G>C

ENST00000580365.1:n.308G>C

ENST00000581378.5:n.295G>C

ENST00000581562.5:n.525-315G>C

ENST00000583312.5:c.577G>C

ENST00000583760.1:n.359G>C

NM_000018.3:c.577G>C

NM_001033859.2:c.511G>C

NM_001270447.1:c.646G>C

NM_001270448.1:c.349G>C

NM_001033859.3:c.511G>C

NM_001270447.2:c.646G>C

NM_001270448.2:c.349G>C

Uncertain Significance

PP4_Moderate PP3 PM2_Supporting

PM5 PM3

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.577G>C variant in ACADVL is a missense variant predicted to cause substitution of glycine by arginine at amino acid 193 (p.Gly193Arg). This variant has been described in several reportedly affected individuals, and at least one individual displayed VLCAD enzyme levels <20% of controls which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 25834949, 25737446). The variant has been described not confirmed in trans to distinct uncertain variants and has also been described in the homozygous state in an individual who did not meet PP4 criteria and was therefore unable to be counted toward PM3 data (PMIDs: 25834949, 25737446, 17999356, 16950999, 25737446, 24305961,16435213, 25834949). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021).

PP4_Moderate

At least one patient with this variant displayed enzyme levels <20% of controls which is highly specific for VLCAD (PP4_Moderate), PMID 25834949, 25737446

PP3

The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PM5

p.Gly193Asp also a VUS

PM3

Detected presumed in trans with c.272C>A; p.Pro91Gln (Variation ID: 932744-VUS), not evaluated by VCEP. Detected in homozygous state but patient does not meet PP4 (PMID: 24305961). Detected not confirmed in trans with I413R, but only described at protein level (not cDNA level), so cannot use PM3 (PMID: 16950999).

Approved on: 2022-12-14

Published on: 2022-12-14

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