Submissions for variant NM_000256.3(MYBPC3):c.1961G>A (p.Arg654His)

dbSNP: rs1800565

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035456	SCV000059104	uncertain significance	not specified	2019-08-29	criteria provided, single submitter	clinical testing	The p.Arg654His variant in MYBPC3 has been reported in 1 individual with HCM (Moolman-Smook 1998) and 0.016% (3/17976) East Asian chromosomes by gnomAD. Functional studies suggest that this variant may impact the protein; though, it is not clear whether this would result in disease (Moolman-Smook 1998, Idowu 2003). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None.
Ambry Genetics	RCV000251228	SCV000320588	uncertain significance	Cardiovascular phenotype	2022-03-09	criteria provided, single submitter	clinical testing	The c.1961G>A (p.R654H) alteration is located in exon 21 (coding exon 21) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1961, causing the arginine (R) at amino acid position 654 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000465385	SCV000546408	uncertain significance	Hypertrophic cardiomyopathy	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 654 of the MYBPC3 protein (p.Arg654His). This variant is present in population databases (rs1800565, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9541115). ClinVar contains an entry for this variant (Variation ID: 42588). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 12386147). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770342	SCV000901776	uncertain significance	Cardiomyopathy	2017-08-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770342	SCV001345900	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 654 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In vitro functional studies have shown that this variant is likely to affect intramolecular interactions (PMID: 12386147, 12787675). This variant has been reported in an individual affected with hypertrophic cardiomyopathy and in his three asymptomatic relatives (PMID: 9541115, 11447480). This variant has been identified in 6/249152 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002490475	SCV002779410	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000465385	SCV004842417	uncertain significance	Hypertrophic cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 654 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In vitro functional studies have shown that this variant is likely to affect intramolecular interactions (PMID: 12386147, 12787675). This variant has been reported in an individual affected with hypertrophic cardiomyopathy and in his three asymptomatic offsprings (PMID: 9541115, 11447480). This variant has also been identified in 6/249152 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.