Submissions for variant NM_000018.4(ACADVL):c.1269+1G>A

dbSNP: rs773401248

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000671502	SCV002769783	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-14	reviewed by expert panel	curation	The c.1269+1G>A variant in ACADVL, also published as IVS12+1G>A, occurs within the canonical splice donor site (+/- 1,2) of intron 12. It is predicted to cause skipping of biologically-relevant-exon 12/20, resulting in an in-frame deletion (removes amino acids 395-423) that is predicted to escape nonsense mediated decay (PVS1_Moderate). This variant has been described without an additional ACADVL variant in 3 individuals identified by newborn screen, identified in an unknown phase to a variant of uncertain significance in two individuals, and has also been identified occurring in the homozygous state in an individual identified by newborn screen (PM3_Supporting, PMIDs: 32793418, 30194637, 25834949, 21932095, 21531094). The individual who carried the c.1269+1G>A variant in the homozygous state also displayed reduced VLCAD enzyme activity, which is highly specific for very long chain acyl CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate, PMID: 25834949). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European (Non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PVS1_Moderate, PM3_Supporting, PP4_Moderate, PM2_Supporting (VCEP specifications version 1; approved November 8, 2021)
Counsyl	RCV000671502	SCV000796484	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2017-12-18	criteria provided, single submitter	clinical testing
Invitae	RCV000671502	SCV001376995	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-06-04	criteria provided, single submitter	clinical testing	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: 555644). This variant is also known as IVS12+1G>A. Disruption of this splice site has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 21932095, 25834949). This variant is present in population databases (rs773401248, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 12 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	RCV000671502	SCV001983477	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-09-22	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1269+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 4e-06 in 251452 control chromosomes. c.1269+1G>A has been reported in the literature as a homozygous genotype in at-least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency, as an uninformative genotype in at-least one individual and in individuals with a carrier genotype (without a second allele specified) (example, Hoffmann_2012, Diekman_2015, Hesse_2018, Maguolo_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete loss of VLCAD activity and long chain-fatty acid oxidation flux (example, Diekman_2015). Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000671502	SCV004212659	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-09-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000671502	SCV002088788	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-07-20	no assertion criteria provided	clinical testing