Submissions for variant NM_000018.4(ACADVL):c.1908dup (p.Ile637fs)

dbSNP: rs1555529204

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673345	SCV000798534	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2018-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000673345	SCV003844440	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-02-08	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1908dupC (p.Ile637HisfsX53) causes a frameshift located in the last exon, therefore it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a part of the 655 amino acid long protein, and replacing it with an incorrect sequence, ultimately resulting in an extension of the protein. The variant was absent in 251410 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1908dupC in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. At least one truncating variant downstream from this position (c.1918_1921delGCCT / p.Ala640Trpfs*39) has been reported in an affected individual (who carried a pathogenic second variant), and patient derived skin fibroblasts were demonstrated to have >90% fatty acid oxidation (FAO) deficiency compared to control cells (PMID: 20060901). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000673345	SCV004633933	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the ACADVL gene (p.Ile637Hisfs*53). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the ACADVL protein and extend the protein by 33 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. ClinVar contains an entry for this variant (Variation ID: 557233). This variant disrupts a region of the ACADVL protein in which other variant(s) (p.Val642Met) have been determined to be pathogenic (PMID: 31031081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.