ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2374T>C (p.Trp792Arg) (rs187830361)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621159 SCV000740020 likely pathogenic Cardiovascular phenotype 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Blueprint Genetics RCV000030283 SCV000264035 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-09-21 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000030283 SCV000190376 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
GeneDx RCV000223788 SCV000208089 likely pathogenic not provided 2017-04-11 criteria provided, single submitter clinical testing The W792R likely pathogenic variant in the MYBPC3 gene has been reported previously in multiple individuals in association with HCM (Van Driest et al., 2004; Theis et al., 2009; Pan et al., 2012; Bos et al., 2014; Murphy et al., 2016), and has been observed in several unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. This variant has also been reported in a 19 year old male with autopsy-negative, exertion-related sudden unexplained death who underwent exome sequencing (Anderson et al., 2016), although this individual harbored an additional variant in the DSG2 gene and segregation data was not provided. W792R has been reported to segregate with HCM in at least two relatives from one family (Pan et al., 2012), and was found to segregate with HCM in one relative from a different family tested at GeneDx. Additionally, it is classified in ClinVar as a likely pathogenic/pathogenic variant by multiple clinical laboratories in association with cardiomyopathy (SCV000052950.1, SCV000059137.4, SCV000264035.1, SCV000280236.1, SCV000284226.1; Landrum et al., 2016). W792R was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, W792R occurs at a position that is conserved across species and is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts that W792R is damaging to the structure/function of the protein. Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Integrated Genetics/Laboratory Corporation of America RCV000030283 SCV000052950 likely pathogenic Primary familial hypertrophic cardiomyopathy 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000228493 SCV000284226 pathogenic Hypertrophic cardiomyopathy 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 792 of the MYBPC3 protein (p.Trp792Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs187830361, ExAC no frequency). This variant has been reported in several individuals affected with hypertropic cardiomyopathy (PMID: 15519027, 19808356, 24793961, 23074333, 27532257). ClinVar contains an entry for this variant (Variation ID: 36605). A computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be pathogenic. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant has been reported in several individuals affected with HCM and is predicted to affect protein function. For these reasons, it has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000228493 SCV000059137 likely pathogenic Hypertrophic cardiomyopathy 2017-11-28 criteria provided, single submitter clinical testing The p.Trp792Arg variant in MYBPC3 has been previously identified in at least 19 individuals with HCM and segregated with disease in 1 affected relative (Theis 2 009, Pan 2012, LMM data). This variant has also been reported in ClinVar (Variat ion ID 36605). It has been identified in 1/8316 European chromosomes by the NHLB I Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs187830361 ). Tryptophan (Trp) at position 792 is highly conserved in mammals and across ev olutionarily distant species and the change to arginine (Arg) was predicted to b e pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jo rdan 2011). In summary, although additional studies are required to fully establ ish its clinical significance, the p.Trp792Arg variant is likely pathogenic. ACM G/AMP Criteria applied: PS4; PM2; PP3.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223788 SCV000280236 likely pathogenic not provided 2014-12-07 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp792Arg in the MYBPC3 gene. Given sufficient case data and lack in the general population, we consider this variant likely disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been seen in at least 8 unrelated individuals with HCM (not including this patient). The one published case was reported by Van Driest et al (2004), who identified the variant in 1 of 389 individuals studied with HCM. Segregation data was not reported in this study. The same group later reported this variant in two individuals, though it is unclear if they were related to each or if one of them overlaps with the prior report (Theis et al 2009). There are no other reported missense variants at this codon or within 10 codons of position 792 (Cardiogenomics, Google, Van Driest et al 2004). This is a non conservative amino acid change with a non polar, neutral Tryptophan replaced with a polar, positive Arginine. Tryptophan is conserved at codon 792 across species. In silico analysis (PolyPhen) predicts the amino acid change to be probably damaging to protein structure/function, and Mutation Taster predicts disease-causing. Analysis with a sarcomere-specific PolyPhen tool predicts the variant to be pathogenic. In total, the variant has been seen in 1 of 6,596 published controls, laboratory controls, and publicly available general population samples. It was not seen in 200 ethnically diverse control individuals analyzed by Van Driest et al (2004). GeneDx did not see this variant in 100 Caucasian individuals and 100 African American individuals. The variant was recently reported online in 1 of 4158 European-American individuals and 0 of 2038 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of Oct. 19, 2013). The phenotype of that individual is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Of note, other HCM-causing variants have been seen at similar frequencies in that dataset. There is no missense variation at codon 792 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Oct 19, 2015).

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