ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.1538C>T (p.Thr513Ile) (rs281865467)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487292 SCV000343086 uncertain significance not provided 2016-06-19 criteria provided, single submitter clinical testing
GeneDx RCV000487292 SCV000568781 likely pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing The T513I variant in the ANO5 gene has been reported previously in a large family with gnathodiaphyseal dysplasia (Marconi et al., 2013). The T513I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T513I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret T513I as a likely pathogenic variant.
Invitae RCV000553314 SCV000645892 uncertain significance Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 513 of the ANO5 protein (p.Thr513Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with gnathodiaphyseal dyplasia in a single multigenerational family (PMID: 23047743). It was observed in 7 affected individuals and was not observed in 14 unaffected individuals.. ClinVar contains an entry for this variant (Variation ID: 288853). Experimental studies have shown that this missense change enhances the activation of the ANO5 protein, allowing for current generation at low calcium concentrations (PMID: 29124309). 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.

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