ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11934G>A (p.Met3978Ile) (rs794728826)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769807 SCV000901233 likely pathogenic Cardiomyopathy 2015-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000182888 SCV000235277 pathogenic not provided 2011-11-28 criteria provided, single submitter clinical testing This mutation is denoted p.Met3978Ile (M3978I) at the protein level and c.11934 G>A at the cDNA level. The Met3978Ile mutation in the RYR2 gene has been reported previously in three individuals diagnosed with CPVT (Krahn AD, et al., 2009; van der Werf et al., 2011; Makanjee et al., 2009), including a 27 year-old female who experienced unexplained cardiac arrest and was subsequently found to have exercise-induced polymorphic ventricular tachycardia (Krahn AD, et al., 2009). Met3978Ile results in a conservative amino acid substitution, however this residue is highly conserved across mammalian species. Met3978Ile is located in the channel region mutation hot spot within the RYR2 gene and a mutation in nearby codon (Asp3977Tyr) has been reported in association with CPVT, further supporting the functional importance of this region of the protein (Medeiros-Domingo A et al., 2009). The Met3978Ile mutation was not detected in up to 200 alleles from control individuals of African American ancestry tested at GeneDx, indicating it is not a common benign variant in this population. In addition, the NHLBI ESP Exome Variant reports that the Met3978Ile mutation was not detected in at least 3,531 individuals of Caucasians and African American backgrounds. The variant is found in CPVT panel(s).

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