ClinVar Miner

Submissions for variant NM_001698.2(AUH):c.719C>T (p.Ala240Val) (rs769894315)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000635279 SCV000756674 uncertain significance 3-Methylglutaconic aciduria type 1 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 240 of the AUH protein (p.Ala240Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs769894315, ExAC 0.003%). This variant has been reported in combination with another AUH variant in an individual affected with 3-methylglutaconic aciduria (PMID: 12655555). Experimental studies have shown that this missense change causes abrogation of GALT enzyme activity leading to a slight decrease in respiratory complex abundance (PMID: 16640564, 24598254). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000635279 SCV000916267 uncertain significance 3-Methylglutaconic aciduria type 1 2018-10-15 criteria provided, single submitter clinical testing The AUH c.719C>T (p.Ala240Val) variant is a missense variant that has been reported in one study, in which it is found in a compound heterozygous state with a second frameshift variant in an individual with 3-methylglutaconic aciduria type 1 (MGA1). This individual presented with vomiting, insomnia, persistent crying, self-mutilation, and hepatomegaly and responded well to dietary L-carnitine (Ly et al. 2003). The p.Ala240Val variant was absent from 176 control chromosomes but is reported at a 0.000047 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies in E. coli showed that the p.Ala240Val variant reduced enzyme activity to 9% of the wildtype protein (Mack et al. 2006), and overexpressing AUH carrying the p.Ala240Val variant in a human bone cell line significantly lowered the 3-MG-CoA hydratase enzyme activity of AUH (Richman et al. 2014). Based on the evidence, the p.Ala240Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for 3-methylglutaconic aciduria type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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