Submissions for variant NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala)

gnomAD frequency: 0.00124  dbSNP: rs150149784

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001086185	SCV004037587	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-09-26	reviewed by expert panel	curation	The NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala) in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 273 (p. Gly273Ala). The highest population minor allele frequency in gnomAD v3.1.2 is 0.003621 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (>=0.0035) for BS1, and therefore meets this criterion (BS1). At least one patient with this variant displayed an increased C14:1 level, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Supporting, PMID: 24503138), from whom a pathogenic variant was also identified with unknown phase (PM3 point 0.5, PM3_Supporting, PMID: 24503138). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID: 32778825). The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to conflicting 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: BS1, PP4_Supporting, PM3_Supporting, PP3)
GeneDx	RCV000185714	SCV000238637	uncertain significance	not provided	2020-10-26	criteria provided, single submitter	clinical testing	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: 24503138)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086185	SCV000654969	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2025-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001086185	SCV001282783	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001086185	SCV001365199	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.818G>C (NP_000009.1:p.Gly273Ala) [GRCH38: NC_000017.11:g.7222242G>C] 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
Revvity Omics, Revvity	RCV001086185	SCV003822469	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398920	SCV004122908	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.818G>C (p.Gly273Ala) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251436 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) phenotype (0.0029), suggesting that the variant may be a benign polymorphism found primarily in populations of African or African-American origin. c.818G>C has been reported in the literature as a VUS in individuals identified as positive for VLCADD by newborn screening programs in the United States, where it has mostly been reported as an uninformative genotype (i.e. zygosity not specified) and in an individual who harbored two additional variants (one pathogenic) but where phase was unspecified/unknown (e.g. Merritt_2014, Miller_2015, Adhikari_2020). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 24503138, 26385305). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001086185	SCV004562680	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-16	criteria provided, single submitter	clinical testing	The ACADVL c.818G>C; p.Gly273Ala variant (rs150149784) is reported in the literature in an individual affected with very-long chain acyl-CoA dehydrogenase deficiency who carries two other ACADVL variants, one of which is known to be pathogenic (Merritt 2014). This variant is also reported in the heterozygous state in an individual in a large inborn errors of metabolism cohort (Adhikari 2020), and is reported in ClinVar (Variation ID: 203574). This variant is found in the African/African-American population with an allele frequency of 0.34% (86/24964 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.933). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Adhikari AN et al. The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020 Sep;26(9):1392-1397. PMID: 32778825. Merritt JL 2nd et al. Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab. 2014 Apr;111(4):484-92. PMID: 24503138.
Mayo Clinic Laboratories, Mayo Clinic	RCV000185714	SCV005412630	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	BS1, PP3