Submissions for variant NM_001035.3(RYR2):c.13735C>T (p.His4579Tyr)

dbSNP: rs794728830

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182893	SCV000235282	uncertain significance	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The H4579Y variant of uncertain significance in the RYR2 gene has been previously reported in association with CPVT (Larsen et al., 2013; Broendberg et al., 2017). Larsen et al. (2013) originally reported this variant in a 34 year-old woman who died suddenly during physical activity. Cascade genetic testing revealed that the patient's mother, maternal aunt, and maternal uncle each harbored H4579Y, yet after Cardiology evaluation of all three relatives, only the maternal aunt met clinical criteria for CPVT (Larsen et al., 2013). More recently, Broendberg et al. (2017) identified H4579Y in a proband presenting with sudden cardiac death; familial testing confirmed the variant was present in seven symptomatic relatives and three asymptomatic relatives, although specific clinical information and relatives' relationship to the proband were not provided. H4579Y is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H4579Y 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the H4579Y variant 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). Nevertheless, this variant lacks observation in a significant number of affected individuals, informative segregation data, and functional evidence, which would further clarify its pathogenicity.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004593998	SCV005086042	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and gain of function are known mechanisms of disease in this gene and are associated with catecholaminergic polymorphic ventricular tachycardia 1 (MIM#604772) and left ventricular non-compaction (PMIDs: 12459180, 27646203, 29477366, 31875585, 33500567). Loss of function has been reported for ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (MIM#115000), however dominant negative mechanism has not been excluded (PMID: 33536282). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Penetrance for CPVT is estimated to be 60-70% (PMID: 23549275). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ryanodine Receptor TM 4-6 domain (DECIPHER). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. Two alternative changes, p.(His4579Asn) and p.(His4579Gln), have been reported as VUS and likely pathogenic in ClinVar, respectively. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as VUS by a clinical laboratory (ClinVar). Additionally, this variant been classified as likely pathogenic in the literature and has been observed in a family with CPVT (PMIDs: 22222782, 28237968). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant has been identified in a family with CPVT where familial testing confirmed the variant was present in seven symptomatic individuals and three asymptomatic individuals (PMID: 28237968). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign