Submissions for variant NM_000256.3(MYBPC3):c.478C>T (p.Arg160Trp)

gnomAD frequency: 0.00047  dbSNP: rs193068692

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000167985	SCV000054777	benign	Hypertrophic cardiomyopathy	2018-04-05	criteria provided, single submitter	research
CSER _CC_NCGL, University of Washington	RCV000148685	SCV000190412	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151168	SCV000198975	likely benign	not specified	2014-05-01	criteria provided, single submitter	clinical testing	The Arg160Trp variant has been identified in one Japanese proband with late-onse t sporadic HCM and was absent from 200 control chromosomes (Anan 2007). However, the variant has now been identified by our laboratory in 8 individuals (4 DCM, HCM) 4 of whom (1 DCM, 3 HCM) carried a second variant which could be responsibl e for disease. Because HCM and DCM are caused by different defects at the cellul ar level, it is currently believed that the same variant is unlikely to cause bo th cardiomyopathies. In addition, at least 3/8 probands are of minority races (2 Hispanic, 1 Asian, 3 unspecified, 2 white) suggesting this variant may be a ben ign variant more common to a racial subpopulation. In summary, the occurrence of the Arg160Trp variant in HCM as well as DCM probands, its frequent presence wit h additional variants, and identification in minority races argues against a hig hly penetrant pathogenic role.
GeneDx	RCV000151168	SCV000207997	benign	not specified	2016-05-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167985	SCV000218633	benign	Hypertrophic cardiomyopathy	2025-01-29	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202872	SCV000257655	uncertain significance	Dilated cardiomyopathy 1A	2015-05-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001093943	SCV000372408	likely benign	Hypertrophic cardiomyopathy 4	2018-03-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000327033	SCV000372409	likely benign	Left ventricular noncompaction 10	2018-03-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Athena Diagnostics	RCV000151168	SCV000614142	likely benign	not specified	2017-05-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621271	SCV000736504	benign	Cardiovascular phenotype	2017-02-17	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.
Color Diagnostics, LLC DBA Color Health	RCV000777607	SCV000913474	likely benign	Cardiomyopathy	2018-03-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151168	SCV000919805	benign	not specified	2018-09-10	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.478C>T (p.Arg160Trp) results in a non-conservative amino acid change located in one of the Immunoglobulin-like domains (IPR007110) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 200008 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.0099 in the gnomAD database, including 2 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.478C>T, has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy, however these data do not allow any conclusion about variant significance. Moreover, co-occurrences with other pathogenic MYBPC3 variants have been reported (e.g. Zou2013: c.2308+1G>C and c.3137delC (T1046fs); Fourey 2017: c.109G>T (p.Gly37ter)), providing supporting evidence for a benign role. In one HCM family lack of co-segregation with the disease was also reported (Kadota 2015). One functional study reported that the variant does not cause aberrant splicing (Ito 2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign x4, likely benign x2, VUS x1). Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777607	SCV001332769	benign	Cardiomyopathy	2022-12-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003221823	SCV003916714	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	MYBPC3: BS2
All of Us Research Program, National Institutes of Health	RCV000167985	SCV005430077	likely benign	Hypertrophic cardiomyopathy	2024-09-27	criteria provided, single submitter	clinical testing