ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.5170G>A (p.Glu1724Lys) (rs794728740)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182731 SCV000235115 pathogenic not provided 2015-04-27 criteria provided, single submitter clinical testing p.Glu1724Lys (E1724K) GAG>AAG: c.5170 G>A in exon 37 of the RYR2 gene (NM_001035.2). Postma et al (2005) identified the Glu1724Lys mutation in one female patient diagnosed with CPVT in childhood and this mutation was also identified in this patient's affected daughter. The Glu1724Lys mutation was absent from 400 control alleles from individuals of Northern European ancestry (Postma et al, 2005). In addition, the Glu1724Lys mutation was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. Glu1724Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine. The closest pathogenic mutation reported in association with CPVT is Glu1837Lys (Medeiros-Domingo et al, 2009). However, other genetic and environmental factors influence disease expression and severity, and some mutation carriers may never become symptomatic. The variant is found in CPVT panel(s).
Invitae RCV001221018 SCV001393038 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-07-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1724 of the RYR2 protein (p.Glu1724Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with catecholaminergic polymorphic ventricular tachycardia (CPVT; PMID: 28237968) and has been reported in several individuals with clinical features or diagnosis of CPVT (PMID: 16272262, 22787013, 29032884, 26114861). ClinVar contains an entry for this variant (Variation ID: 201254). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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