ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.779C>T (p.Thr260Met) (rs113994168)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020080 SCV000220919 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2014-11-25 criteria provided, single submitter literature only
GeneDx RCV000429481 SCV000511943 pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing The T260M missense variant identified in the ACADVL gene has been reported previously in association with VLCAD deficiency (Andresen et al., 1996).
Invitae RCV000020080 SCV000654968 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 260 of the ACADVL protein (p.Thr260Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs113994168, ExAC <0.01%). This variant has been reported in several individuals affected with very-long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 19327992, 20060901, 21932095). ClinVar contains an entry for this variant (Variation ID: 21024). Experimental studies have shown that this missense change reduces VLCAD enzymatic activity (PMID: 9973285, 17374501, 19327992). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000020080 SCV000916407 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-07-02 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000020080 SCV001156588 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-10-14 criteria provided, single submitter clinical testing 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). It is reported as pathogenic 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 algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. Additionally, functional characterization of the variant protein in patient fibroblasts demonstrate significantly decreased enzymatic activity (Andresen 1996, Andresen 1999, Hoffman 2012, Laforet 2009). 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. 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. 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. 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. 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. 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.
Baylor Genetics RCV000020080 SCV001163798 pathogenic Very long chain acyl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
GeneReviews RCV000020080 SCV000040378 pathologic Very long chain acyl-CoA dehydrogenase deficiency 2011-09-22 no assertion criteria provided curation Converted during submission to Pathogenic.

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