ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2459G>A (p.Arg820Gln) (rs2856655)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000525220 SCV000198854 likely pathogenic Hypertrophic cardiomyopathy 2018-08-07 criteria provided, single submitter clinical testing The p.Arg820Gln variant in MYBPC3 has been reported in 16 individuals with HCM, segregated with disease in 6 affected relatives from 3 families (Konno et al. 20 03, Nanni et al. 2003, Alders et al. 2003, Shimizu et al. 2003, Konno et al. 200 6, Kapplinger et al. 2014, and Hodatsu et al. 2014, LMM data), and has also been reported in ClinVar (Variation ID 8617). Additionally, it has been identified i n 3/111676 of European chromosomes and 1/17248 of East Asian chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs2 856655). Animal models (zebrafish) support that this variant causes HCM (Hodatsu et al. 2014). In summary, this variant meets criteria to be classified as patho genic for HCM in an autosomal dominant manner based upon presence in multiple af fected individuals, segregation studies, absence from controls and functional ev idence. ACMG/AMP Criteria Applied: PS4, PM2, PS3_Moderate, PP1_Moderate.
GeneDx RCV000158159 SCV000208094 likely pathogenic not provided 2016-07-20 criteria provided, single submitter clinical testing The R820Q variant in the MYBPC3 gene has been reported previously in several unrelated patients with HCM and was not reported in at least 1,568 healthy control alleles (Konno et al., 2003; Nanni et al., 2003; Page et al., 2012; Lopes et al., 2013; Hodatsu et al., 2014; Kapplinger et al., 2014). R820Q was reported in seven families with HCM and one family with DCM in which all affected relatives available for testing harbored the R820Q variant (Konno et al., 2003). The patient with DCM reported by Konno et al. was subsequently reported to have possible burnt out" HCM (Shimizu et al., 2005). R820Q has also been reported in three unrelated individuals who harbored additional variants in cardiomyopathy-related genes (Nanni et al., 2003; Lopes et al., 2013; Hodatsu et al., 2014). The R820Q variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R820Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. 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, missense variants in this residue (R820W) and in nearby residues (R810L, R810H, K811R) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. Therefore, this variant is likely pathogenic. "
Invitae RCV000525220 SCV000623557 pathogenic Hypertrophic cardiomyopathy 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 820 of the MYBPC3 protein (p.Arg820Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs2856655, ExAC 0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy, segregating with the disease in many families, and has been found to be  a common cause of the disease in Japan, although it has also been reported in other populations (PMID: 12628722, 12951062, 18929575, 18761664, 20542340, 20800588, 22112859,  22267749, 25281569, 27483260, 28087566). This variant is also known as c.2491G>A in the literature. Experimental studies have shown that this missense change leads to ventricular thickening when expressed in zebrafish embryos (PMID: 25281569). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009148 SCV000029365 pathogenic Familial hypertrophic cardiomyopathy 4 2005-02-01 no assertion criteria provided literature only

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