ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.711_712del (p.Cys237fs)

dbSNP: rs2071256607
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV001200780 SCV003853584 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-01-10 reviewed by expert panel curation The NM_000018.4:c.711_712del (p.Cys237fs) variant in ACADVL, also known as p.(Cys237TrpfsTer15) and del710-11, is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 8/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs 9973285, 11590124). The c.711_712del variant has been reported in the literature in one confirmed homozygous individual with an increased acylcarnitine level and severely reduced ACADVL enzyme activity, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_moderate, PM3_supporting; PMIDs: 11124787, 9973285). This variant is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1, PM2_supporting, PM3_supporting, PP4_moderate (ACADVL VCEP specifications version 1; approved November 8, 2021).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV001200780 SCV001364901 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.711_712delTG (NP_000009.1:p.Cys237TrpfsTer15) [GRCH38: NC_000017.11:g.7222040_7222041delTG] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 9973285. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001200780 SCV001748710 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2021-06-28 criteria provided, single submitter clinical testing Variant summary: ACADVL c.711_712delTG (p.Cys237TrpfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251584 control chromosomes (gnomAD and publication data). c.711_712delTG has been reported in the literature in one homozygous individual with a severe neonatal presentation and cardiomyopathy (Andresen_1999, Touma_2001). This patients sample showed ACADVL enzyme activity was severely decreased to 2% of control levels and no normal sized mutant ACADVL mRNA was observed. Additionally, this patients undiagnosed sisters died early in life and parent were both heterozygous for this variant. These data indicate that the variant may be associated with disease. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001200780 SCV004213610 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-02-10 criteria provided, single submitter clinical testing
Invitae RCV001200780 SCV004297750 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-12-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys237Trpfs*15) in the ACADVL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). This variant is also known as del710-11. ClinVar contains an entry for this variant (Variation ID: 932827). For these reasons, this variant has been classified as Pathogenic.

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