rs149116708
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000018.4(ACADVL):c.1198G>A(p.Val400Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V400V) has been classified as Likely benign.
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1198G>A | p.Val400Met | missense_variant | 12/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1198G>A | p.Val400Met | missense_variant | 12/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251466Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727240
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:2Uncertain:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 16, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 14, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 400 of the ACADVL protein (p.Val400Met). This variant is present in population databases (rs149116708, gnomAD 0.0009%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 26385305, 27538624). ClinVar contains an entry for this variant (Variation ID: 551143). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
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.1198G>A (NP_000009.1:p.Val400Met) [GRCH38: NC_000017.11:g.7223659G>A] 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: PP4, BP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at