Submissions for variant NM_000018.4(ACADVL):c.1751+1G>A

dbSNP: rs1567569262

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000761524	SCV000891657	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2017-12-30	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000761524	SCV003443706	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-07-06	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. ClinVar contains an entry for this variant (Variation ID: 623375). Disruption of this splice site has been observed in individual(s) with a positive newborn screening result for ACADVL-related disease (PMID: 23700290). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 18 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	RCV000761524	SCV005423401	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-10-04	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1751+1G>A 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ACADVL function. Several computational tools predict a significant impact on normal splicing: Four 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 228528 control chromosomes. c.1751+1G>A has been reported in the literature in a compound heterozygous individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Chien_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23700290). ClinVar contains an entry for this variant (Variation ID: 623375). Based on the evidence outlined above, the variant was classified as likely pathogenic.