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.481G>A (p.Ala161Thr)

CA8337740

324987 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0cf92352-c3ea-4314-84ff-2be7307616c9

Approved on: 2024-08-13

Published on: 2024-08-13

HGVS expressions

NM_000018.4:c.481G>A

NM_000018.4(ACADVL):c.481G>A (p.Ala161Thr)

NC_000017.11:g.7221541G>A

CM000679.2:g.7221541G>A

NC_000017.10:g.7124860G>A

CM000679.1:g.7124860G>A

NC_000017.9:g.7065584G>A

NG_007975.1:g.6708G>A

NG_008391.2:g.3510C>T

ENST00000356839.10:c.481G>A

ENST00000322910.9:c.*436G>A

ENST00000350303.9:c.415G>A

ENST00000356839.9:c.481G>A

ENST00000543245.6:c.550G>A

ENST00000577191.5:n.558G>A

ENST00000577433.5:n.689G>A

ENST00000577857.5:n.297G>A

ENST00000579286.5:n.662G>A

ENST00000579886.2:c.319G>A

ENST00000580365.1:n.212G>A

ENST00000581378.5:c.199G>A

ENST00000581562.5:n.525-411G>A

ENST00000582166.1:n.462G>A

ENST00000583312.5:c.481G>A

ENST00000583760.1:n.263G>A

NM_000018.3:c.481G>A

NM_001033859.2:c.415G>A

NM_001270447.1:c.550G>A

NM_001270448.1:c.253G>A

NM_001033859.3:c.415G>A

NM_001270447.2:c.550G>A

NM_001270448.2:c.253G>A

Likely Pathogenic

PP4_Moderate PP3 PM3 PM2_Supporting

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.481G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 161 (p.Ala161Thr) and is also known as Ala121Thr by traditional nomenclature. The variant has been described in at least three individuals who displayed increased C14:1 acylcarnitines, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 28755359, 26385305, 16488171). In at least one of these individuals, the variant was confirmed as occurring in trans to a variant the ACADVL VCEP has classified as likely pathogenic and not confirmed in trans to a variant the ACADVL VCEP has classified as pathogenic (PM3, 1.5 points, PMID: 16488171, 16950999). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001975 in Admixed American 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 0.773, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). 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: PP4_Moderate, PM3, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021).

PP4_Moderate

The variant has been described in at least three individuals who displayed increased C14:1 acylcarnitines, which is highly specific for VLCAD deficiency (PP4_Moderate; PMIDs: 28755359, 26385305, 16488171).

PP3

The computational predictor REVEL gives a score of 0.773, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3).

PM3

Confirmed in trans to variant VCEP approved as LP.

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001975 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

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