ClinVar Miner

Submissions for variant NM_000018.4(ACADVL):c.1246G>A (p.Ala416Thr) (rs118204018)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000001700 SCV000832737 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 416 of the ACADVL protein (p.Ala416Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs118204018, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with a myopathic form of very-long chain acyl-CoA dehydrogenase deficiency (PMID: 11158518). In addition, this variant has been reported in combination with other ACADVL variants in individuals affected with very-long chain acyl-CoA dehydrogenase deficiency (PMID: 11914034, 15210884). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 1633). Experimental studies have shown that this missense change affected the activity of the encoded enzyme although a significant residual activity of 10-20% was retained (PMID: 11158518). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000001700 SCV000915779 likely pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2018-11-22 criteria provided, single submitter clinical testing The ACADVL c.1246G>A (p.Ala416Thr) variant has been reported in at least four patients in a compound heterozygous state, two of whom had mild manifestation of VLCAD deficiency (Fukao et al. 2001; Takusa et al. 2002; Brown et al. 2014; Hesse et al. 2018). The p.Ala416Thr variant was absent from 100 controls and is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies used transient expression of the p.Ala416Thr variant and showed residual acyl-CoA dehydrogenase activity of 10-20% of wild type (Fukao et al. 2001). Based on the evidence, the ACADVL p.Ala416Thr variant is classified as likely pathogenic for VLCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000001700 SCV000021856 pathogenic Very long chain acyl-CoA dehydrogenase deficiency 2001-02-01 no assertion criteria provided literature only

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