Submissions for variant NM_000018.4(ACADVL):c.1748C>T (p.Ser583Leu)

gnomAD frequency: 0.00001  dbSNP: rs1085307648

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000665031	SCV002769770	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-15	reviewed by expert panel	curation	The NM_000018.4(ACADVL): c.1748C>T (p.Ser583Leu) variant in ACADVL is a missense variant predicted to cause substitution of serine by leucine at amino acid 583 (p.Ser583Leu). This variant has been detected in two individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency. Of those individuals, both were homozygous for the variant; Moreover, this variant was co-detected with c.848T>C (p.Val283Ala) variant with unknown phase (PM3 point 1.5, PMIDs 32518924, 23774949) (PM3). At least two patients with this variant in homozygous state displayed clinical phonotypes, NBS abnormalities and/or increased C14:1 levels, which is highly specific for VLCAD deficiency (PP4_Supporting, PMIDs 32518924). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 26385305).The highest population minor allele frequency in gnomAD v2.1.1 is 0.000034 in South Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.674, which is neither above nor below the thresholds predicting a damaging or benign impact on ACADVL function. Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM3, PM2_Supporting, PP4_Supporting.
Counsyl	RCV000665031	SCV000789086	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2017-01-06	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000665031	SCV001364941	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1748C>T (NP_000009.1:p.Ser583Leu) [GRCH38: NC_000017.11:g.7224711C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 15210884. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000665031	SCV001472293	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-11-03	criteria provided, single submitter	clinical testing	The ACADVL c.1748C>T; p.Ser583Leu variant (rs1085307648) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase (VLCAD) deficiency, some of whom had significantly lower VLCAD enzyme activity (Bujan 2014, Campbell 2005, Miller 2015, Ohashi 2004). This variant is reported in ClinVar (Variation ID: 550315), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 583 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.674). Additionally, another variant at this codon (c.1748C>G; p.Ser583Trp) has been reported in individuals with VLCAD deficiency (Miller 2015). Based on available information, this variant is considered to be pathogenic. References: Bujan N et al. Characterization of CoQ10 biosynthesis in fibroblasts of patients with primary and secondary CoQ10 deficiency. J Inherit Metab Dis. 2014 Jan;37(1):53-62. PMID: 23774949. Campbell CD et al. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica. 2005 Dec;90(12 Suppl):ECR45. PMID: 16464760. 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. Ohashi Y et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004 Jun 22;62(12):2209-13. PMID: 15210884.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665031	SCV002309913	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-11-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 583 of the ACADVL protein (p.Ser583Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 15210884, 16464760, 23774949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as S543L. ClinVar contains an entry for this variant (Variation ID: 550315).
GeneDx	RCV004719926	SCV005325453	likely pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 16464760, 26385305, 20480395, 15210884, 32518924, 23774949, 9599005)
Fulgent Genetics, Fulgent Genetics	RCV000665031	SCV005650631	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-19	criteria provided, single submitter	clinical testing