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.1066A>G (p.Ile356Val)

CA200650

193541 (ClinVar)

Gene: ACADVL
Condition: very long chain acyl-CoA dehydrogenase deficiency
Inheritance Mode: Autosomal recessive inheritance
UUID: 61e40fb3-21f4-43ac-af6c-3116fb9fcaf6
Approved on: 2022-09-23
Published on: 2022-09-23

HGVS expressions

NM_000018.4:c.1066A>G
NM_000018.4(ACADVL):c.1066A>G (p.Ile356Val)
NC_000017.11:g.7222854A>G
CM000679.2:g.7222854A>G
NC_000017.10:g.7126173A>G
CM000679.1:g.7126173A>G
NC_000017.9:g.7066897A>G
NG_007975.1:g.8021A>G
NG_008391.2:g.2197T>C
ENST00000356839.10:c.1066A>G
ENST00000322910.9:c.*1021A>G
ENST00000350303.9:c.1000A>G
ENST00000356839.9:c.1066A>G
ENST00000543245.6:c.1135A>G
ENST00000578824.5:n.215A>G
ENST00000582379.1:n.450A>G
ENST00000583858.5:c.95A>G
ENST00000585203.6:n.7A>G
NM_000018.3:c.1066A>G
NM_001033859.2:c.1000A>G
NM_001270447.1:c.1135A>G
NM_001270448.1:c.838A>G
NM_001033859.3:c.1000A>G
NM_001270447.2:c.1135A>G
NM_001270448.2:c.838A>G
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Uncertain Significance

Met criteria codes 2
BA1 PP4_Moderate
Not Met criteria codes 5
PM1 PM5 BP4 PM3_Supporting PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
ACADVL VCEP
The c.1066A>G variant in ACADVL has been reported in multiple probands with abnormal newborn screening, but only one with a reported enzyme activity of 38% in lymphocytes (PP4; PMIDs: 30194637, 26385305, 23867825, 31031081, 27209629). In one probands it was observed with a likely pathogenic variant, however not confirmed in trans (PM3_supporting, PMID: 2720962). The highest population minor allele frequency in gnomAD v2.1.1 is 0.009786 in the African population with 3 total homozygotes, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). Computational prediction tools and conservation analysis do not agree on the predicted impact of this variant. In summary, this variant has conflicting evidence and is therefore of uncertain significance for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: PP4; PM3_supporting; BA1
Met criteria codes
BA1
Allele frequency is 0.009786 with 3 homozygotes in the African population, >0.7%
PP4_Moderate
The majority of probands observed with this variant have abnormal newborn screening (highest value C14:1 of 0.83), however the only value for VLCAD enzyme activity was in a carrier (38% residual activity in lymphocytes).
Not Met criteria codes
PM1
Although the variant could lead to a less stable protein, partial functionality plus the lack of any critical domains does not meet this criteria
PM5
Only amino acid change observed has not been published
BP4
REVEL score of 0.621
PM3_Supporting
This variant has been observed not confirmed in-trans with two variants, one pathogenic and one likely pathogenic. Only one likely pathogenic proband has enough data to be counted for PP4 (PMID: 31031081, Proband 14) but 0.25 points fails to meet the criteria.
PP3
REVEL score of 0.621
Curation History
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