ClinVar Miner

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

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Total submissions: 5
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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).
GeneReviews RCV000020080 SCV000040378 pathologic Very long chain acyl-CoA dehydrogenase deficiency 2011-09-22 no assertion criteria provided curation Converted during submission to 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.
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.

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