Submissions for variant NM_000018.4(ACADVL):c.1077_1077+1delinsCAC

dbSNP: rs1057516686

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000411230	SCV002576735	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-09-20	reviewed by expert panel	curation	The c.1077_1077+1delinsCAC; p.Val360Thrfs*2 variant in ACADVL occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of biologically-relevant-exon 10, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMIDs: 9973285, 11590124). This variant is absent from gnomAD population database v2.1.1 (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PP4, PMID: 9973285). The ACADVL Variant Curation Expert Panel VCEP classified the variant as pathogenic based on (PVS1,PM2_supporting,PP4).
Counsyl	RCV000411230	SCV000486065	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2016-03-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725401	SCV000700964	pathogenic	not provided	2015-10-15	criteria provided, single submitter	clinical testing
Invitae	RCV000411230	SCV000773894	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-06-20	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 9973285). This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 10 (c.1077_1077+1delinsCAC) of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411230	SCV000916405	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2018-10-22	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1077_1077+1delinsCAC is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244794 control chromosomes (gnomAD). The variant, c.1077_1077+1delinsCAC, has been reported in the literature in one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency in whom no second allele was reported so the exact genotype could not be inferred (Andresen_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000411230	SCV001364912	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1077_1077+1delinsCAC (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222865_7222866delinsCAC] 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
PreventionGenetics, part of Exact Sciences	RCV003401388	SCV004103676	likely pathogenic	ACADVL-related condition	2023-09-20	criteria provided, single submitter	clinical testing	The ACADVL c.1077_1077+1delinsCAC variant is predicted to result in an in-frame deletion and insertion. This change is predicted to abolish the canonical splice donor site. This variant was reported in an individual with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (Andresen et al. 1999. PubMed ID: 9973285; Intron 10 GG>CAC). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Canonical-splice altering variants in ACADVL are expected to be pathogenic, including several others reported at this same splice junction. This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV000411230	SCV004210933	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-09-13	criteria provided, single submitter	clinical testing