ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.230C>T (p.Ala77Val)

dbSNP: rs1060500142
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002522771 SCV000541662 pathogenic Catecholaminergic polymorphic ventricular tachycardia 1 2023-09-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR2 function (PMID: 19913485, 22374134). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 404190). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 16084945; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 77 of the RYR2 protein (p.Ala77Val).
GeneDx RCV001553236 SCV001774066 likely pathogenic not provided 2023-07-02 criteria provided, single submitter clinical testing Published in one family and segregated with both CPVT and ARVC in several relatives (d'Amati et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant may affect calcium release, which is thought to cause arrhythmia (Tang et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 24025405, 19913485, 22221940, 16084945, 25901278, 31112425, 22374134)
Ambry Genetics RCV002446768 SCV002735581 likely pathogenic Cardiovascular phenotype 2019-01-11 criteria provided, single submitter clinical testing The p.A77V variant (also known as c.230C>T), located in coding exon 3 of the RYR2 gene, results from a C to T substitution at nucleotide position 230. The alanine at codon 77 is replaced by valine, an amino acid with similar properties. This variant has been reported in a sudden death case with an arrhythmogenic right ventricular cardiomyopathy phenotype on autopsy and in two relatives with catecholaminergic polymorphic ventricular tachycardia (CPVT) as well as in an aborted cardiac arrest patient with CPVT (d'Amati G et al. Hum. Pathol., 2005 Jul;36:761-7; van der Werf C et al. Heart Rhythm, 2010 Oct;7:1383-9). Functional studies suggest this alteration impacts calcium signaling, but the physiological relevance of this impact is unclear (Tang Y. et al. Circ. Res., 2012 Mar;110(7):968-77). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lobo PA et al. Structure, 2009 Nov;17:1505-14; Tung CC et al. Nature, 2010 Nov;468:585-8; Walpoth BN et al. F1000Res, 2015 Jan;4:29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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