ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.478C>T (p.Arg160Trp) (rs193068692)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621271 SCV000736504 benign Cardiovascular phenotype 2017-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Athena Diagnostics Inc RCV000151168 SCV000614142 likely benign not specified 2017-05-05 criteria provided, single submitter clinical testing
Biesecker Lab/Human Development Section,National Institutes of Health RCV000167985 SCV000054777 benign Hypertrophic cardiomyopathy 2018-04-05 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center 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
Color RCV000777607 SCV000913474 likely benign Cardiomyopathy 2018-03-05 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202872 SCV000257655 uncertain significance Dilated cardiomyopathy 1A 2015-05-05 criteria provided, single submitter clinical testing
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.
Illumina Clinical Services Laboratory,Illumina RCV000366510 SCV000372407 likely benign Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000167985 SCV000372408 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000327033 SCV000372409 likely benign Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000167985 SCV000218633 benign Hypertrophic cardiomyopathy 2018-01-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.

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