Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

Variant: NM_000018.4(ACADVL):c.538G>A (p.Ala180Thr)

CA295584

166641 (ClinVar)

Gene: ACADVL
Condition: very long chain acyl-CoA dehydrogenase deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: bef919f1-3031-42e2-911a-bf0cd70e9570
Approved on: 2022-12-14
Published on: 2022-12-14

HGVS expressions

NM_000018.4:c.538G>A
NM_000018.4(ACADVL):c.538G>A (p.Ala180Thr)
NC_000017.11:g.7221598G>A
CM000679.2:g.7221598G>A
NC_000017.10:g.7124917G>A
CM000679.1:g.7124917G>A
NC_000017.9:g.7065641G>A
NG_007975.1:g.6765G>A
NG_008391.2:g.3453C>T
ENST00000356839.10:c.538G>A
ENST00000322910.9:c.*493G>A
ENST00000350303.9:c.472G>A
ENST00000356839.9:c.538G>A
ENST00000543245.6:c.607G>A
ENST00000577191.5:n.615G>A
ENST00000577433.5:n.746G>A
ENST00000577857.5:n.354G>A
ENST00000579286.5:n.719G>A
ENST00000579886.2:c.376G>A
ENST00000580365.1:n.269G>A
ENST00000581378.5:c.256G>A
ENST00000581562.5:n.525-354G>A
ENST00000582166.1:n.519G>A
ENST00000583312.5:c.538G>A
ENST00000583760.1:n.320G>A
NM_000018.3:c.538G>A
NM_001033859.2:c.472G>A
NM_001270447.1:c.607G>A
NM_001270448.1:c.310G>A
NM_001033859.3:c.472G>A
NM_001270447.2:c.607G>A
NM_001270448.2:c.310G>A
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Uncertain Significance

Met criteria codes 4
PP4_Moderate PP3 PM2_Supporting PM1_Supporting
Not Met criteria codes 1
PM3

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
ACADVL VCEP
The c.538G>A variant in ACADVL is a missense in exon 7 residing within a region of critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PMID:26385305). This variant has been reported in patients affected with very-long chain acyl-CoA dehydrogenase deficiency, and elevated C14:1 (PP4_moderate, PMID: 26385305, 31844625, 32778825). In addition this variant is associated with reduced VLCAD activity measured from patient lymphocytes (PMID: 30194637). This variant has also been found as a compound heterozygote with a second ACADVL variant, however the phase nor pathogenicity of the second variant is unknown at this time (PMID: 31844625, 30194637). The highest population minor allele frequency in gnomAD 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 0.92, 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 VUS for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: (PM1, PM2_Supporting, PP3, PP4_moderate).
Met criteria codes
PP4_Moderate
At least one patient with this variant displayed enzyme levels (activity 3% of normal controls) which is highly specific for VLCAD (PP4_moderate) (PMID 30194637). Enriched in VLCADD; 5 alleles (Miller et al.) 4 alleles: heterozygote 1 allele: with p.V283A
PP3
The computational predictor REVEL gives a score of 0.916, 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).
PM1_Supporting
This variant resides within a region of ACADVL that is defined as a critical functional domain by the ClinGen ACADVL Variant Curation Expert Panel. Specifically the variant is located near the enzyme active site (PMID 26385305)(PM1_supporting).
Specifically the variant is located near the enzyme active site (PMID 26385305) PubMed:26385305
Not Met criteria codes
PM3
Seen with p.R456H in Hesse et al. in one patient with 3% residual enzyme activity in lymphocytes. This variant has not been curated and is conflicting pathogenicity on ClinVar.
Curation History
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