Submissions for variant NM_000018.4(ACADVL):c.751A>G (p.Ser251Gly)

gnomAD frequency: 0.00001  dbSNP: rs749159573

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000373221	SCV000406317	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000373221	SCV000654965	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-08	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 324989). This missense change has been observed in individual(s) with very long chain acyl CoA dehydrogenase deficiency (VLCAD) deficiency confirmed by biochemical assays (PMID: 26937394; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs749159573, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 251 of the ACADVL protein (p.Ser251Gly). For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000373221	SCV001365223	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.751A>G (NP_000009.1:p.Ser251Gly) [GRCH38: NC_000017.11:g.7222080A>G] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM3, PP3, PP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000373221	SCV002050000	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-11-03	criteria provided, single submitter	clinical testing	The ACADVL c.751A>G; p.Ser251Gly (rs749159573) is reported in trans to a pathogenic variant in an infant with VLCAD deficiency (Scott Schwoerer 2015). The variant is reported in the ClinVar database (Variation ID: 324989) and is found in the general population with an overall allele frequency of 0.001% (3/251,484 alleles) in the Genome Aggregation Database. The serine at codon 251 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.978). However, given the lack of clinical and functional data, the significance of the p.Ser251Gly variant is uncertain at this time. References: Scott Schwoerer J et al. Rhabdomyolysis in a neonate due to very long chain acyl CoA dehydrogenase deficiency. Mol Genet Metab Rep. 2015 Mar 30;3:39-41.
Myriad Genetics, Inc.	RCV000373221	SCV002060060	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2021-11-19	criteria provided, single submitter	clinical testing	NM_000018.3(ACADVL):c.751A>G(S251G) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. S251G has been observed in cases with relevant disease (PMID: 26385305, 26937394). Functional assessments of this variant are not available in the literature. S251G has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.751A>G(S251G) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.