ClinVar Genomic variation as it relates to human health

The NM_000018.4(ACADVL): c.779C>T (p.Thr260Met) variant is a missense variant predicted to cause substitution of threonine by methionine at amino acid 260. This variant has been detected in individuals with very long chain acyl CoA dehydrogenase (VLCAD) deficiency and VLCAD enzyme activity of less than 20%, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 8845838, 17374501, 32518924). This variant was found homozygous in two individuals with VLCAD deficiency (PM3, 1.0 point, PMIDs: 9327992, 32518924). Two enzyme activity assays in Cos-7 cells and E.coli showed residual enzyme activity between 3-5% of wildtype indicating that this variant impacts protein function (PMIDs: indicating that this variant impacts protein function (PMID: 9973285, 9973285; PS3_supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 in the non-Finnish European 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 0.875, 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: PM2_Supporting, PM3_moderate, PP3, PP4_Moderate, PS3_supporting (ACADVL VCEP specifications version 1; approved November 9, 2021).

Variant summary: ACADVL c.779C>T (p.Thr260Met) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central 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 2e-05 in 246264 control chromosomes (gnomAD). c.779C>T has been reported in the literature in multiple individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency as both a homozygous and compound heterozygous allele (Liebig_2006, Laforet_2009). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence showing a significant decrease (<10% of normal) in VLCAD activity in patient fibroblasts (Laforet_2009). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

The NM_000018.3:c.779C>T (NP_000009.1:p.Thr260Met) [GRCH38: NC_000017.11:g.7222203C>T] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 8845838. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3

Published functional studies found T260M is associated with significantly reduced enzyme activity (Andresen et al., 1999; Goetzman et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20480395, 17374501, 25087612, 20060901, 9973285, 8845838, 21932095, 27943070, 30194637, 16950999, 20301763, 10077518, 19327992, 31589614)

The ACADVL c.779C>T; p.Thr260Met variant (rs113994168), also known as Thr220Met, has been reported in multiple individuals diagnosed with very long chain acyl-CoA dehydrogenase deficiency, often found in-trans with another pathogenic variant (Andresen 1996, Andresen 1999, Gobin-Limballe 2010, Laforet 2009, Mathur 1999). Additionally, functional characterization of the variant protein in patient fibroblasts demonstrate significantly decreased enzymatic activity (Andresen 1996, Andresen 1999, Hoffman 2012, Laforet 2009). This variant is reported in ClinVar (Variation ID: 21024) and observed in the general population at a low overall frequency of 0.002% (5/246264 alleles) in the Genome Aggregation Database. The threonine at residue 260 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.875). Based on available information, this variant is considered pathogenic. References: Andresen B et al. Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. Hum Mol Genet. 1996; 5(4):461-72. PMID: 8845838. Andresen B et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999; 64(2):479-94. PMID: 9973285. Gobin-Limballe S et al. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches. Biochim Biophys Acta. 2010; 1802(5):478-84. PMID: 20060901. Hoffman L et al. VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment. J Inherit Metab Dis. 2012; 35(2):269-77. PMID: 21932095. Laforet P et al. Diagnostic assessment and long-term follow-up of 13 patients with Very Long-Chain Acyl-Coenzyme A dehydrogenase (VLCAD) deficiency. Neuromuscul Disord. 2009; 19(5):324-9. PMID: 19327992. Mathur A et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999; 99(10):1337-43. PMID: 10077518.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 260 of the ACADVL protein (p.Thr260Met). This variant is present in population databases (rs113994168, gnomAD 0.003%). This missense change has been observed in individual(s) with very-long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 19327992, 20060901, 21932095). ClinVar contains an entry for this variant (Variation ID: 21024). 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%. Experimental studies have shown that this missense change affects ACADVL function (PMID: 9973285, 17374501, 19327992). For these reasons, this variant has been classified as Pathogenic.

ACMG categories: PS5,PM1,PM2,PM3,PP3,PP4,PP5,BP1