ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1806_1807del (p.Leu602_Cys603insTer)

dbSNP: rs796051917
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen RCV000666299 SCV002576741 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2022-09-22 reviewed by expert panel curation The c.1806_1807del (p.Leu602_Cys603insTer) variant in ACADVL is a frameshift variant that may cause loss of function of the protein due to impacting FAD interaction, however it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_moderate). Two siblings with this variant displayed C14:1 levels >0.8 µM, which is highly specific for VLCAD deficiency (PP4_moderate; PMID: 27209629). These same individuals were compound heterozygous for this variant and the pathogenic frameshift variant c.1173dup, however neither was confirmed in trans (PM3_supporting; PMID: 27209629). Finally, the variant segregates with VLCAD deficiency in the affected sibling (PP1; PMID: 27209629). 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 VLCAD deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL VCEP: PVS1_moderate; PP4_moderate; PM3_supporting; PP1; PM2_supporting. Pilot Specifications; Approved on 05/12/2020.
GeneDx RCV000185740 SCV000238668 pathogenic not provided 2013-07-02 criteria provided, single submitter clinical testing The c.1806_1807delCT mutation causes the replacement of a Cysteine codon with a Stop codon at position 603, denoted p.Cys603Ter. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, it is predicted to be a pathogenic mutation. The variant is found in ACADVL panel(s).
Counsyl RCV000666299 SCV000790568 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2017-03-31 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000666299 SCV001364989 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2019-11-01 criteria provided, single submitter clinical testing The NM_000018.3:c.1806_1807delCT (NP_000009.1:p.Cys603Ter) [GRCH38: NC_000017.11:g.7224863_7224864del] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3
Invitae RCV000666299 SCV002241217 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-08-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Arg615*) have been determined to be pathogenic (PMID: 10431122). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 203593). This premature translational stop signal has been observed in individual(s) with clinical features of very long-chain acyl-CoA dehydrogenase deficiency (PMID: 26385305, 27209629). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys603*) in the ACADVL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the ACADVL protein.
Baylor Genetics RCV000666299 SCV004216880 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2023-06-21 criteria provided, single submitter clinical testing
Natera, Inc. RCV000666299 SCV002088814 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2020-07-14 no assertion criteria provided clinical testing

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