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Variant: NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter)

CA233425

166638 (ClinVar)

Gene: ACADVL
Condition: very long chain acyl-CoA dehydrogenase deficiency
Inheritance Mode: Autosomal recessive inheritance
UUID: a955db98-1e3b-463b-8b12-e2456a6ad0eb
Approved on: 2022-09-22
Published on: 2022-09-22

HGVS expressions

NM_000018.4:c.65C>A
NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter)
NC_000017.11:g.7220124C>A
CM000679.2:g.7220124C>A
NC_000017.10:g.7123443C>A
CM000679.1:g.7123443C>A
NC_000017.9:g.7064167C>A
NG_007975.1:g.5291C>A
NG_008391.2:g.4927G>T
ENST00000356839.10:c.65C>A
ENST00000322910.9:c.*20C>A
ENST00000350303.9:c.65C>A
ENST00000356839.9:c.65C>A
ENST00000543245.6:c.134C>A
ENST00000577191.5:n.142C>A
ENST00000577857.5:n.155C>A
ENST00000578269.5:n.172C>A
ENST00000578421.1:n.199C>A
ENST00000579286.5:n.172C>A
ENST00000579886.2:c.65C>A
ENST00000580263.5:n.155C>A
ENST00000581562.5:n.112C>A
ENST00000582056.5:n.155C>A
ENST00000582356.5:n.190C>A
ENST00000583312.5:c.65C>A
ENST00000584103.5:c.65C>A
NM_000018.3:c.65C>A
NM_001033859.2:c.65C>A
NM_001270447.1:c.134C>A
NM_001270448.1:c.-164C>A
NM_001033859.3:c.65C>A
NM_001270447.2:c.134C>A
NM_001270448.2:c.-164C>A
More

Pathogenic

Met criteria codes 5
PM3 PM2_Supporting PS3_Supporting PP4_Moderate PVS1
Not Met criteria codes 7
PM5 PM4 PM1 BP7 BP1 BP2 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
ACADVL VCEP
The NM_000018.4(ACADVL):c.65C>A (p.Ser22Ter) variant in ACADVL is a nonsense predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1: PMIDs 9973285, 11590124). Immunoblot shows no VLCAD enzyme on patients' fibroblasts (PMID 10790204)(PS3_Supporting). Metabolic activity as measured by MTT assay showed reduced proliferation rate in primary patient fibroblasts and CRISPR knock-in Hs27 cells when compared to normal (PMID:32010688) (PS3_Supporting). This variant has been detected in at least 35 individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, 34 of whom were homozygous for the variant (PMID: 28980192, 32010688, 10790204), and one compound heterozygous for a likely pathogenic without phase confirmation (PMID: 24801231)(PM3, Total points assigned = 1.5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Multiple cases are observed with elevated C14:1 from NBS and reduced ACADVL activity, which is highly specific for VLCADD (PMID: 28980192,10790204)(PP4_Moderate). The ACADVL Variant Curation Expert Panel VCEP classified this variant as pathogenic based on PVS1,PS3_Supporting, PM3, PM2_Supporting, PP4_Moderate.
Met criteria codes
PM3
PM3 is met; Total points assigned = 1.5; Choose conservative PM3 score of 1.0 Points: multiple homozygous cases = max 1.0 point; one unknown phase compound het = 0.5
PM2_Supporting
PM2_Supporting is met; variant is not observed in gnomAD (MAF=0%, 0 alleles out of 172340), ExAC, 1K and ESP.
PS3_Supporting
PS3_Supporting is met; Immunoblot shows no VLCAD enzyme on patients' fibroblasts (PMID 10790204). Metabolic activity as measured by MTT assay showed reduced proliferation rate in primary patient fibroblasts and CRISPR knockin Hs27 cells when compared to normal (PMID:32010688).
PP4_Moderate
PP4_Moderate is met; Multiple VLCADD cases with elevated C14:1 from NBS (no values or cutoffs mentioned) (PMID: 28980192); 0% enzyme activity in patient fibroblast for C16 (PMID: 10790204).
PVS1
PVS1 is met; Nonsense in a gene where loss-of-function variants have been described in multiple VLCADD patients; predicted NMD with > 10% loss of protein length
Not Met criteria codes
PM5
PM5 is not met; Variant is a nonsense.
PM4
PM4 is not met; Variant is nonsense.
PM1
PM1 is not met; Variant is a nonsense.
BP7
BP7 is not met; Variant is a nonsense
BP1
BP1 is not met; variant is a nonsense.
BP2
BP2 is not met; The variant has not been observed in cis with a pathogenic variant in ACADVL.
PS1
PS1 is not met, Variant is a nonsense and there is no other recorded nucleotide change in this codon that will result in a nonsense.
Curation History
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