rs375284481
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePP3PM3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.481G>A (NM_000018.4) variant in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 161 (p.Ala161Thr) and is also known as Ala121Thr by traditional nomenclature. The variant has been described in at least three individuals who displayed increased C14:1 acylcarnitines, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 28755359, 26385305, 16488171). In at least one of these individuals, the variant was confirmed as occurring in trans to a variant the ACADVL VCEP has classified as likely pathogenic and not confirmed in trans to a variant the ACADVL VCEP has classified as pathogenic (PM3, 1.5 points, PMID:16488171, 16950999). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001975 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.773, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337740/MONDO:0008723/021
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.481G>A | p.Ala161Thr | missense_variant | 7/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.481G>A | p.Ala161Thr | missense_variant | 7/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251452Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135918
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461822Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16AN XY: 727214
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74336
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 161 of the ACADVL protein (p.Ala161Thr). This variant is present in population databases (rs375284481, gnomAD 0.02%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 16488171, 16950999; Invitae). This variant is also known as A121V. ClinVar contains an entry for this variant (Variation ID: 324987). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The ACADVL c.481G>A (p.Ala161Thr) variant has been reported in one study in a compound heterozygous state with another missense variant in one individual with very long-chain-acyl-CoA dehydrogenase (VLCAD) deficiency (Boneh et al. 2006). The variant was also identified in a heterozygous state in the unaffected father. Control data are unavailable for this variant which is reported at a frequency of 0.00017 in the total population of the Exome Aggregation Consortium. The Ala161 residue is conserved. The evidence for this variant is limited. The p.Ala161Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, 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.481G>A (NP_000009.1:p.Ala161Thr) [GRCH38: NC_000017.11:g.7221541G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 16488171. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_000018.3(ACADVL):c.481G>A(A161T) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. A161T has been observed in cases with relevant disease (PMID: 16488171, 16950999, 20480395). Functional assessments of this variant are not available in the literature. A161T has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.481G>A(A161T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at