rs398123079
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000018.4(ACADVL):āc.1001T>Gā(p.Met334Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,904 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M334I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1001T>G | p.Met334Arg | missense_variant | 10/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1001T>G | p.Met334Arg | missense_variant | 10/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251308Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135870
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461764Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727188
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 25, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 15, 2022 | The ACADVL c.1001T>G; p.Met334Arg variant (rs148584617) is reported in the literature in multiple individuals affected with very long chain acyl-coA dehydrogenase deficiency (Miller 2015, Pena 2016). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 92270), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The methionine at codon 334 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). However, given the lack of clinical and functional data, the significance of the p.Met334Arg variant is uncertain at this time. References: Miller MJ et al. Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45. PMID: 26385305. Pena LD et al. Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016 Aug;118(4):272-81. PMID: 27209629. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 334 of the ACADVL protein (p.Met334Arg). This variant is present in population databases (rs398123079, gnomAD 0.004%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 27209629; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92270). 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 | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Nov 01, 2019 | The NM_000018.3:c.1001T>G (NP_000009.1:p.Met334Arg) [GRCH38: NC_000017.11:g.7222789T>G] variant in ACADVL gene is interpretated to be Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PS3, PM1, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 27, 2021 | NM_000018.3(ACADVL):c.1001T>G(M334R) is a missense variant classified as a variant of uncertain significance in the context of very-long-chain acyl-CoA dehydrogenase deficiency. M334R has been observed in cases with relevant disease (PMID: 27209629). Functional assessments of this variant are not available in the literature. M334R has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, there is insufficient evidence to classify NM_000018.3(ACADVL):c.1001T>G(M334R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2021 | Reported in multiple individuals with an abnormal newborn screening result for VLCAD deficiency in whom a second ACADVL variant was not identified (Miller et al. 2015); Reported in an asymptomatic individual diagnosed with VLCAD deficiency via molecular testing and acylcarnitine profile analysis following an abnormal newborn screening result. This individual also had a second missense variant identified in the ACADVL gene although the phase of the two variants was not reported (Pena et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 27209629, 26385305) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 19, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 02, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 21, 2020 | Variant summary: ACADVL c.1001T>G (p.Met334Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain of 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 1.6e-05 in 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1001T>G has been reported in the literature in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency following newborn screening results (Miller_2015, Pena_2016). These reports however, 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. Five ClinVar submitters (evaluation after 2014) cite 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