Variant: NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg)

CA285287

92270 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 136ddbdd-c4c2-436f-bb57-d41b0c6d36dc

Approved on: 2024-08-13

Published on: 2025-01-28

HGVS expressions

NM_000018.4:c.1001T>G
NM_000018.4(ACADVL):c.1001T>G (p.Met334Arg)
NC_000017.11:g.7222789T>G
CM000679.2:g.7222789T>G
NC_000017.10:g.7126108T>G
CM000679.1:g.7126108T>G
NC_000017.9:g.7066832T>G
NG_007975.1:g.7956T>G
NG_008391.2:g.2262A>C
ENST00000356839.10:c.1001T>G
ENST00000322910.9:c.*956T>G
ENST00000350303.9:c.935T>G
ENST00000356839.9:c.1001T>G
ENST00000543245.6:c.1070T>G
ENST00000578824.5:n.150T>G
ENST00000581378.5:c.719T>G
ENST00000582379.1:n.385T>G
ENST00000583858.5:c.30T>G
NM_000018.3:c.1001T>G
NM_001033859.2:c.935T>G
NM_001270447.1:c.1070T>G
NM_001270448.1:c.773T>G
NM_001033859.3:c.935T>G
NM_001270447.2:c.1070T>G
NM_001270448.2:c.773T>G

Uncertain Significance

• Met criteria codes: PP4 PP3 PM2_Supporting

• Not Met criteria codes: BA1 BS1 PM3 PM5

Expert Panel

ACADVL VCEP

Criteria Specification Information

Evidence submitted by expert panel

ACADVL VCEP

The c.1001T>G (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of methionine by arginine at amino acid 334 (p.Met334Arg). At least one patient with this variant displayed abnormal newborn screen and follow-up acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, which is highly specific for VLCAD (PP4_supporting, PMID: 27209629) Additionally, at least six individuals with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003874 for the European (Non-Finnish) 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 0.945, 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 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: PM2_Supporting, PP3, PP4 (ACADVL VCEP specifications version 1; approved November 9, 2021)

Met criteria codes

• PP4: At least one patient with this variant displayed abnormal newborn screen and follow-up acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, which is highly specific for VLCAD (PP4_supporting, PMID: 27209629) Additionally, at least six individuals with this variant was identified by newborn screen, but this information is insufficient to use toward classification (PMID: 26385305).
• PP3: REVEL score is 0.945
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003874 for the European (Non-Finnish) and 0.000005932 for the European (Non-Finnish) in gnomAD v4.1.0

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: PM3 not met_ The Variant was reported with (c.1844G>A; p.R615Q). However, the variant is reported in ClinVar as Likely Benign
• PM5: Other Missense changes at this residue (p.Met334) have been seen but are not determined to be pathogenic (p.Met334Thr, p.Met334Val, p.Met334Ile).