Submissions for variant NM_000018.4(ACADVL):c.1076C>T (p.Ala359Val)

gnomAD frequency: 0.00003  dbSNP: rs539029862

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652045	SCV000773911	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 359 of the ACADVL protein (p.Ala359Val). This variant is present in population databases (rs539029862, gnomAD 0.003%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 26385305, 27209629; internal data). 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: 541725). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001200112	SCV001370985	likely pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001200112	SCV001811859	likely pathogenic	not provided	2021-06-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26385305, 27535533, 29111448, 27209629)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000652045	SCV002049300	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2021-09-03	criteria provided, single submitter	clinical testing	The ACADVL c.1076C>T; p.Ala359Val variant (rs539029862) is reported in the literature in multiple individuals with abnormal newborn screening suggestive of VLCAD deficiency (Miller 2015, Pena 2016). This variant is also reported in ClinVar (Variation ID: 541725). This variant is found in the general population with an overall allele frequency of 0.001% (4/281,292 alleles) in the Genome Aggregation Database. The alanine at codon 359 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.755). Based on available information, this variant is considered to be likely pathogenic. References: Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PMID: 27209629.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000652045	SCV003923208	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-24	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1076C>T (p.Ala359Val) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249948 control chromosomes (gnomAD). c.1076C>T has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Miller_2015, Pena_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=1) or likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000652045	SCV004216857	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-02-21	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000652045	SCV005051766	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-02-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000652045	SCV005650593	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-04-04	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000652045	SCV001365076	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	flagged submission	clinical testing	The NM_000018.3:c.1076C>T (NP_000009.1:p.Ala359Val) [GRCH38: NC_000017.11:g.7222864C>T] 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