Submissions for variant NM_000018.4(ACADVL):c.1678+3_1678+6del

dbSNP: rs759135941

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000801366	SCV004037592	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-09-27	reviewed by expert panel	curation	The c.1678+3_1678+6del variant in ACADVL is an intronic variant which occurs in intron 16. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold. The computational splicing predictor SpliceAI gives a score of 0.85 for donor loss, predicting that the variant disrupts the donor splice site of intron 16 of ACADVL (PP3). This variant has been detected in an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency (internal lab contributor). At least one patient with this variant displayed abnormal NBS with follow-up Plasma Acylcarnitine analysis consistent with VLCAD deficiency, which is highly specific for VLCAD deficiency (PP4_moderate, Internal lab contributors). This variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PP3, PP4_moderate. (ACADVL VCEP specifications version 1; approved November 9, 2021)
Invitae	RCV000801366	SCV000941140	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the ACADVL gene. It does not directly change the encoded amino acid sequence of the ACADVL protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs759135941, gnomAD 0.01%). This variant has been observed in individual(s) with VLCAD deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 646976). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000801366	SCV001158116	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-01-27	criteria provided, single submitter	clinical testing	The ACADVL c.1678+3_1678+6delAAGT variant (rs759135941), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in Latino population with an allele frequency of 0.012% (4/34,526 alleles) in the Genome Aggregation Database. This is an intronic variant deleting highly conserved nucleotides, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by significantly weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.1678+3_1678+6delAAGT variant is uncertain at this time.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000801366	SCV001365119	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1678+3_1678+6delAAGT (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7224555_7224558delAAGT] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3
GeneDx	RCV002225734	SCV002504654	likely pathogenic	not provided	2022-03-11	criteria provided, single submitter	clinical testing	Reported in a cohort of individuals with inborn errors of metabolism (Adhikari et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32778825)
Natera, Inc.	RCV000801366	SCV001459263	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing