Submissions for variant NM_000018.4(ACADVL):c.1567G>A (p.Gly523Arg)

gnomAD frequency: 0.00066  dbSNP: rs139425622

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725179	SCV000334673	uncertain significance	not provided	2015-08-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000272698	SCV000406326	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2018-01-12	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000370922	SCV000602379	uncertain significance	not specified	2017-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV000272698	SCV000654938	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 523 of the ACADVL protein (p.Gly523Arg). This variant is present in population databases (rs139425622, gnomAD 0.08%). This missense change has been observed in individual(s) with sudden infant death (PMID: 28747690; Invitae). ClinVar contains an entry for this variant (Variation ID: 282928). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000272698	SCV001365211	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1567G>A (NP_000009.1:p.Gly523Arg) [GRCH38: NC_000017.11:g.7224355G>A] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant dose not meet any evidence codes reported in the ACMG guidelines.
Genome-Nilou Lab	RCV000272698	SCV001781306	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2021-07-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000370922	SCV002103715	uncertain significance	not specified	2022-02-19	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.1567G>A (p.Gly523Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 250394 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (0.00042 vs 0.0029), allowing no conclusion about variant significance. c.1567G>A has been reported in the literature as a non-informative genotype and/or as uncertain classification in at-least two reports, one in an individual with sudden unexpected death (SUD) (example, Oshima_2017) and another in an individual with a history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER) and normal responses to halothane and caffeine (example, Gardner_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Very Long Chain Acyl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000272698	SCV002779397	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-05-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519124	SCV003632727	uncertain significance	Inborn genetic diseases	2021-09-02	criteria provided, single submitter	clinical testing	The c.1567G>A (p.G523R) alteration is located in exon 16 (coding exon 16) of the ACADVL gene. This alteration results from a G to A substitution at nucleotide position 1567, causing the glycine (G) at amino acid position 523 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000272698	SCV003822482	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-06-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000272698	SCV004040739	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-01-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000725179	SCV004224308	uncertain significance	not provided	2023-05-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000272698	SCV001459258	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing