Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000018.4(ACADVL):c.1593dup (p.Ser532fs)

CA16616934

417917 (ClinVar)

Gene: ACADVL

Condition: very long chain acyl-CoA dehydrogenase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b146c2e2-4adc-43eb-9737-7a034a774b43

HGVS expressions

NM_000018.4:c.1593dup

NM_000018.4(ACADVL):c.1593dup (p.Ser532fs)

NC_000017.11:g.7224381dup

CM000679.2:g.7224381dup

NC_000017.10:g.7127700dup

CM000679.1:g.7127700dup

NC_000017.9:g.7068424dup

NG_007975.1:g.9548dup

NG_008391.2:g.671dup

NG_033038.1:g.15165dup

ENST00000356839.10:c.1593dup

ENST00000322910.9:c.*1548dup

ENST00000350303.9:c.1527dup

ENST00000356839.9:c.1593dup

ENST00000542255.6:n.451dup

ENST00000543245.6:c.1662dup

ENST00000578319.5:n.88dup

ENST00000578711.1:n.877dup

ENST00000578809.5:n.165dup

ENST00000579391.1:n.201dup

ENST00000579425.5:n.709dup

ENST00000579546.1:n.332dup

ENST00000579894.5:n.380dup

ENST00000582450.1:n.101dup

ENST00000583074.5:n.214dup

ENST00000583850.5:n.368dup

ENST00000583858.5:n.524dup

ENST00000585203.6:n.784dup

NM_000018.3:c.1593dup

NM_001033859.2:c.1527dup

NM_001270447.1:c.1662dup

NM_001270448.1:c.1365dup

NM_001033859.3:c.1527dup

NM_001270447.2:c.1662dup

NM_001270448.2:c.1365dup

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PM2_Supporting

PP4 PM3

Evidence Links 0

Expert Panel

ACADVL VCEP

Criteria Specification Information

Criteria Specification: ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ACADVL VCEP

The c.1593dup (p.Ser532GlufsTer30) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as LIKELY PATHOGENIC for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_Supporting (ClinGen ACADVL VCEP specifications version#1; 09-05-2022).

PVS1

PVS1 is met. The c.1593dup (p.Ser532GlufsTer30) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124).

PM2_Supporting

PM2_Supporting is met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4

PP4 not met. This variant has been detected in at least one individual identified by abnormal newborn screening or presumed positive on newborn screening for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with no reported follow-up plasma acylcarnitine or enzyme activity (PMID: 26385305).

PM3

PM3 not met at any strength. Variant reported as 2 alleles; no mention if found in heterozygous, homozygous or compound heterozygous state.

Approved on: 2022-09-05

Published on: 2022-12-13

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