Submissions for variant NM_000256.3(MYBPC3):c.2761C>G (p.Gln921Glu)

gnomAD frequency: 0.00006  dbSNP: rs367729718

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000721105	SCV000208122	likely benign	not provided	2020-07-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18809796, 24510615, 28679633, 28706299)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084330	SCV001003458	likely benign	Hypertrophic cardiomyopathy	2025-01-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000988537	SCV001138292	likely benign	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186906	SCV001353517	likely benign	Cardiomyopathy	2018-11-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372626	SCV004086545	benign	Cardiovascular phenotype	2023-08-01	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488407	SCV004241658	likely benign	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2761C>G (p.Gln921Glu) results in a conservative amino acid change located in a Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 242486 control chromosomes, predominantly at a frequency of 0.002 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2761C>G has been reported in the literature in individuals affected with Cardiomyopathy (e.g., Maron_2008, Fokstuen_2014, Thompson_2021, Stava_2022), but also in the literature in several ostensibly healthy controls (e.g., Kapplinger_2014, Juang_2021). These reports therefore do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with another pathogenic variant has been reported (MYBPC3 c.1504C>T, p.R502W; Maron_2008), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34026292, 18809796, 35653365, 23590259, 24510615, 33782553). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000721105	SCV000280243	likely benign	not provided	2016-08-22	no assertion criteria provided	provider interpretation	re-assessment prompted by MAF in ExAC most common in east asians AF 0.00209839 18/8578 alleles overall: AF 0.00017774, 21/118152 alleles did not re-review case data, only ExAC data. -p.Gln921Glu (c.2761 C>G) in exon 27 of the MYBPC3 gene (NM_000256.3) This variant has been reported in multiple studies ranging from associations with phenotype to control subjects. Maron et al. (2008) reported this variant in a patient with hypertrophic cardiomyopathy. The patient also harbored a well-characterized mutation in the MYBPC3 gene (p.Arg502Trp) which we at Stanford classify as very likely disease causing. This variant was also found in one patient who had a structurally normal echocardiogram and a clinical diagnosis of long QT syndrome with a QT interval ranging from 130-550 ms and syncope (Fokstuen, S., 2014). A study performed by Dr. Ackerman's group at Mayo clinic sequenced healthy control samples from diverse populations found this variant in one individual who was sequenced for nine hypertrophic cardiomyopathy genes including MYH7, MYL2, MYL3, MYBPC3, ACTC1, TNNC1, TNN13, TNNT2, and TPM1. It was not reported in combination with any other variations in these genes (Kapplinger et al., 2013). Another patient was reported with a different change at this residue (Q921L). However segregation analysis was not performed on this variant therefore making pathogenicity unclear (Brito et al., 2012).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000721105	SCV001957635	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000721105	SCV001963484	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000721105	SCV001975273	uncertain significance	not provided		no assertion criteria provided	clinical testing