Submissions for variant NM_000018.4(ACADVL):c.1077+1G>A

dbSNP: rs140989450

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000666633	SCV002576766	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-07-12	reviewed by expert panel	curation	The c.1077+1G>A 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). The highest population minor allele frequency in gnomAD is 0.00006 in the African population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) meeting this criterion (PM2_Supporting). This variant has been reported once as a heterozygote associated with very-long chain acyl-CoA dehydrogenase deficiency (PMID: 26385305). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on PVS1+PM2_supporting.
GeneDx	RCV000520772	SCV000616633	pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Published in an individual with an abnormal newborn screening result for VLCAD deficiency; a second variant was not identified (Miller et al. 2015); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 11590124, 26385305, 9973285, 25338548, 30194637)
Counsyl	RCV000666633	SCV000790956	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2017-04-17	criteria provided, single submitter	clinical testing
Invitae	RCV000666633	SCV001227842	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 448981). Disruption of this splice site has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 25338548, 30194637). This variant is present in population databases (rs140989450, gnomAD 0.0009%).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000666633	SCV001364974	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1077+1G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222866G>A] 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
Revvity Omics, Revvity	RCV000666633	SCV002021096	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-09-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666633	SCV004216835	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-07-11	criteria provided, single submitter	clinical testing