Submissions for variant NM_000018.4(ACADVL):c.308A>G (p.Lys103Arg)

gnomAD frequency: 0.00391  dbSNP: rs140566084

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001122813	SCV002576744	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-28	reviewed by expert panel	curation	The c.308A>G variant in ACADVL is a missense variant predicted to cause substitution of lysine by arginine at amino acid 103 (p.Lys103Arg). This variant has been reported in one individual with elevated C14:1 levels, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4; PMID: 27209629). The highest population minor allele frequency in gnomAD v2.1.1 is 1.2% in the African population, which is higher than the ClinGen ACADVL threshold (0.7%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.35, which is below the threshold of 0.5 indicating that the variant does not predict a damaging effect on ACADVL function (BP4). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for VLCAD deficiency, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4, BA1, BP4 (ACADVL VCEP specifications version 1; approved November 9, 2021). This variant was originally curated September 23, 2022 and the recurated classification was approved by the expert panel on March 28, 2023.
PreventionGenetics, part of Exact Sciences	RCV000241751	SCV000301523	benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV001122813	SCV000654950	benign	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122813	SCV001281577	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001122813	SCV001365175	benign	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.308A>G (NP_000009.1:p.Lys103Arg) [GRCH38: NC_000017.11:g.7220796A>G] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001122813	SCV001473033	benign	Very long chain acyl-CoA dehydrogenase deficiency	2022-03-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508430	SCV001714577	uncertain significance	not provided	2022-02-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001508430	SCV001758002	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000241751	SCV002074306	likely benign	not specified	2022-01-17	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.308A>G (p.Lys103Arg) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251434 control chromosomes, predominantly at a frequency of 0.012 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 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0029), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.308A>G has been reported in the literature as a VUS in settings of newborn/presumptive screening for Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example, Miller_2015). 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 and a predominant consensus as likely benign/benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001508430	SCV004033521	benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ACADVL: BS1, BS2
Natera, Inc.	RCV001122813	SCV001455122	benign	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing