rs375806217
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000018.4(ACADVL):c.1733T>C(p.Met578Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,522,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M578V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1733T>C | p.Met578Thr | missense_variant | 18/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1733T>C | p.Met578Thr | missense_variant | 18/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000858 AC: 12AN: 139926Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000938 AC: 2AN: 213112Hom.: 0 AF XY: 0.00000865 AC XY: 1AN XY: 115568
GnomAD4 exome AF: 0.00000578 AC: 8AN: 1382976Hom.: 0 Cov.: 38 AF XY: 0.00000729 AC XY: 5AN XY: 685908
GnomAD4 genome ? AF: 0.0000857 AC: 12AN: 139994Hom.: 0 Cov.: 32 AF XY: 0.0000445 AC XY: 3AN XY: 67394
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Uncertain:4
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.1733T>C (NP_000009.1:p.Met578Thr) [GRCH38: NC_000017.11:g.7224696T>C] 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 | Invitae | May 22, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 578 of the ACADVL protein (p.Met578Thr). This variant is present in population databases (rs375806217, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. ClinVar contains an entry for this variant (Variation ID: 92280). 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, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2015 | The M578T missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative in that a non-polar Methionine residue is replaced by a polar Threonine residue. This change occurs at a highly conserved position in the ACADVL protein. However, in-silico analysis models are not consistent in their predictions of whether M578T is damaging to the ACADVL protein. Therefore, based on the currently available information it is unclear whether M578T is a disease-causing mutation or a rare benign variant. The variant is found in ACADVL panel(s). - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 05, 2013 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2021 | Variant summary: ACADVL c.1733T>C (p.Met578Thr) results in a non-conservative amino acid change in 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 9.4e-06 in 213112 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1733T>C in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Although this variant has been reported as a VUS with a non-informative genotype (second allele not specified) in at-least one allele belonging to a newborn screen (NBS) or a presumed NBS cohort (Miller_2013). Four 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at