rs140566084
Variant summary
Our verdict is Uncertain significance. Variant got -7 ACMG points: 2P and 9B. BP4BA1PP4_Moderate
This summary comes from the ClinGen Evidence Repository: 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, an acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and a positive fatty acid oxidation probe assay, which are highly specific for 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 April 23, 2024. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337646/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.308A>G | p.Lys103Arg | missense_variant | 5/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.308A>G | p.Lys103Arg | missense_variant | 5/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00375 AC: 571AN: 152192Hom.: 3 Cov.: 33
GnomAD3 exomes AF: 0.00138 AC: 347AN: 251434Hom.: 3 AF XY: 0.00106 AC XY: 144AN XY: 135904
GnomAD4 exome AF: 0.000843 AC: 1232AN: 1461784Hom.: 10 Cov.: 33 AF XY: 0.000755 AC XY: 549AN XY: 727176
GnomAD4 genome ? AF: 0.00378 AC: 576AN: 152310Hom.: 3 Cov.: 33 AF XY: 0.00372 AC XY: 277AN XY: 74484
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Uncertain:1Benign:5
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Apr 23, 2024 | 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, an acylcarnitine profile consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, and a positive fatty acid oxidation probe assay, which are highly specific for 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 April 23, 2024. - |
Benign, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Nov 01, 2019 | 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 - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 28, 2022 | - - |
not provided Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | ACADVL: BS1, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 24, 2022 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 17, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at