chr17-7224355-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_000018.4(ACADVL):c.1567G>A(p.Gly523Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000675 in 1,613,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G523G) has been classified as Likely benign.
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1567G>A | p.Gly523Arg | missense_variant | 16/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1567G>A | p.Gly523Arg | missense_variant | 16/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000624 AC: 95AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000415 AC: 104AN: 250394Hom.: 1 AF XY: 0.000406 AC XY: 55AN XY: 135510
GnomAD4 exome AF: 0.000680 AC: 994AN: 1461656Hom.: 1 Cov.: 33 AF XY: 0.000670 AC XY: 487AN XY: 727114
GnomAD4 genome AF: 0.000624 AC: 95AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43AN XY: 74434
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Uncertain:8
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 04, 2023 | - - |
Uncertain significance, 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.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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 12, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Uncertain significance, 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, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 19, 2022 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 01, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 23, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 25, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 02, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at