Variant: NM_000018.4(ACADVL):c.751A>G (p.Ser251Gly)

CA10640460

324989 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 9e28ea5e-51c4-457d-b1a6-77bc36d3abed

Approved on: 2025-02-25

Published on: 2025-02-25

HGVS expressions

NM_000018.4:c.751A>G
NM_000018.4(ACADVL):c.751A>G (p.Ser251Gly)
NC_000017.11:g.7222080A>G
CM000679.2:g.7222080A>G
NC_000017.10:g.7125399A>G
CM000679.1:g.7125399A>G
NC_000017.9:g.7066123A>G
NG_007975.1:g.7247A>G
NG_008391.2:g.2971T>C
ENST00000356839.10:c.751A>G
ENST00000322910.9:c.*706A>G
ENST00000350303.9:c.685A>G
ENST00000356839.9:c.751A>G
ENST00000543245.6:c.820A>G
ENST00000577191.5:n.828A>G
ENST00000579286.5:n.932A>G
ENST00000580365.1:n.482A>G
ENST00000581378.5:c.469A>G
ENST00000582379.1:n.135A>G
ENST00000583760.1:n.533A>G
NM_000018.3:c.751A>G
NM_001033859.2:c.685A>G
NM_001270447.1:c.820A>G
NM_001270448.1:c.523A>G
NM_001033859.3:c.685A>G
NM_001270447.2:c.820A>G
NM_001270448.2:c.523A>G

Likely Pathogenic

• Met criteria codes: PP3 PM3 PP4_Moderate PM2_Supporting

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The NM_000018.4(ACADVL): c.751A>G (p.Ser251Gly) variant is a missense variant predicted to cause substitution of serine by glycine at amino acid 251. This variant has been detected in one individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. This individual was compound heterozygous for the variant and a pathogenic variant and confirmed in trans by parental testing (1.0 PM3 points, PMID: 26937394, PM3_moderate). At least one patient with this variant displayed NBS C14:1 levels ≥ 1.0 μM and follow-up Plasma Acylcarnitine analysis consistent with VLCADD, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 26937394). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the non-Finnish European 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 0.978, 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: PM2_Supporting, PM3_moderate, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).

Met criteria codes

• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: 1.0 point
• PP4_Moderate: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2_Supporting: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline