Submissions for variant NM_000018.4(ACADVL):c.138+1G>A

gnomAD frequency: 0.00001  dbSNP: rs747351687

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000665642	SCV002538685	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-04-06	reviewed by expert panel	curation	The c.138+1G>A (p.?) (NM_000018.4) variant in ACADVL occurs within the canonical splice acceptor site (+1) of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2/20, 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 v2.1.1 is 0.004% (1/22352 alleles) in SAS population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with this variant in a heterozygous state was positive at NBS or presumed NBS positive; the second allele was not clearly stated (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 11/10/2021).
Counsyl	RCV000665642	SCV000789795	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2017-02-21	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000665642	SCV001364948	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.138+1G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7220198G>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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665642	SCV002050839	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-12-10	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.138+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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.8e-06 in 128992 control chromosomes (gnomAD). c.138+1G>A has been reported in the literature in atleast one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Miller_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665642	SCV003442478	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 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). This variant is present in population databases (rs747351687, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 26385305). ClinVar contains an entry for this variant (Variation ID: 550796). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Fulgent Genetics, Fulgent Genetics	RCV000665642	SCV005650549	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-09	criteria provided, single submitter	clinical testing