ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2686G>A (p.Val896Met) (rs35078470)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757506 SCV000885759 likely benign not provided 2017-09-22 criteria provided, single submitter clinical testing The p.Val896Met variant (rs35078470) has been reported with similar frequencies in cases and controls, and it has been found in multiple affected individuals who also had pathogenic or likely pathogenic variants in other genes that explained the phenotype (Andreasen 2012, Jääskeläinen 2014, Jääskeläine 2002, Keller 2004, Mörner 2003, Richard 2003, Zaragoza 2016). This variant has also been identified in the homozygous state in an unaffected family member who was beyond the expected age of onset of disease (Jääskeläine 2002). Furthermore, the p.Val896Met variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 2.8% in the Finnish European population (identified in 590 out of 20,786 chromosomes; 9 homozygotes), and is classified as benign/likely benign by multiple labs in ClinVar (Variant ID: 42652). Based on the available evidence, the p.Val896Met variant is classified as likely benign.
Ambry Genetics RCV000251320 SCV000318931 benign Cardiovascular phenotype 2016-06-06 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
Biesecker Lab/Human Development Section,National Institutes of Health RCV000143915 SCV000051564 benign Primary familial hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
Blueprint Genetics, RCV000143915 SCV000188788 likely benign Primary familial hypertrophic cardiomyopathy 2014-06-26 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000143915 SCV000190370 likely benign Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
CSER_CC_NCGL; University of Washington Medical Center RCV000204363 SCV000212192 likely benign Hypertrophic cardiomyopathy 2015-03-11 criteria provided, single submitter research
Color RCV000776054 SCV000910681 benign Cardiomyopathy 2018-03-19 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000602093 SCV000744836 benign Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000602093 SCV000733037 benign Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000035521 SCV000228298 likely benign not specified 2015-05-15 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000602093 SCV000743549 likely benign Familial hypertrophic cardiomyopathy 4 2017-07-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000204363 SCV000372318 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035521 SCV000919804 benign not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.2686G>A (p.Val896Met) results in a conservative amino acid change located in the Fibronectin type III of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0064 in 203838 control chromosomes in the gnomAD database, including 16 homozygotes. The observed variant frequency is more than 6-fold above the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is benign. c.2686G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported in multiple individuals tested at LCA (MYBPC3 c.2373dupG, p.Trp792fsX41; MYH7 c.428G>A, p.Arg143Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000204363 SCV000261462 benign Hypertrophic cardiomyopathy 2017-08-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035521 SCV000059171 benign not specified 2015-06-25 criteria provided, single submitter clinical testing p.Val896Met in exon 26 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 10% (68/690) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs35078470).

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