ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2873C>T (p.Thr958Ile) (rs376504548)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000204227 SCV000054764 uncertain significance Hypertrophic cardiomyopathy 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035535 SCV000059185 uncertain significance not specified 2016-07-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr958Ile var iant in MYBPC3 has been reported in 4 individuals with HCM, one of whom carried another pathogenic MYBPC3 variant (Kabaeva 2005, Ehlermann 2008, Adalsteinsdotti r 2014, Bos 2014). In addition, this variant has been identified by our laborato ry in 3 individuals with HCM, (including one infant whose unaffected parent also carried this variant, as well as one adult who also carried a pathogenic MYBPC3 variant (in cis)) and 1 individual with DCM. This variant has been identified i n 7/61564 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /; dbSNP rs376504548). Threonine at position 958 is not conserved in evolution and 1 mammal (Bactrian camel) and multiple bird species h ave an isoleucine (Ile) at this position, suggesting that this change may be tol erated. In addition, this change was predicted to be benign using a computationa l tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, while the cli nical significance of the p.Thr958Ile variant is uncertain, collectively these d ata suggest that it is more likely to be benign.
GeneDx RCV000035535 SCV000208384 likely benign not specified 2017-12-11 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.
Invitae RCV000204227 SCV000260689 uncertain significance Hypertrophic cardiomyopathy 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 958 of the MYBPC3 protein (p.Thr958Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs376504548, ExAC 0.01%) and has been found in one asymptomatic individual (PMID: 23861362). This variant was reported in individuals affected with dilated cardiomyopathy (PMID: 28416588 ) and hypertrophic cardiomyopathy (HCM) (PMID: 15823648, 18957093, 24793961, 25078086, 27532257). However, one pathogenic allele was identified in the MYBPC3 gene in one of these cases, which suggests that this c.2873C>T substitution in MYBPC3 was not the primary cause of disease in this individual. ClinVar contains an entry for this variant (Variation ID: 42664). A computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy, predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). However, this prediction has not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000246190 SCV000320418 uncertain significance Cardiovascular phenotype 2016-12-02 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,Insufficient or conflicting evidence,In silico models in agreement (benign)
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000625022 SCV000743545 uncertain significance Familial hypertrophic cardiomyopathy 4 2016-10-26 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625022 SCV000744832 uncertain significance Familial hypertrophic cardiomyopathy 4 2017-05-31 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148674 SCV000190398 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035535 SCV000280250 uncertain significance not specified 2013-04-09 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.Thr958Ile (c.2873 C>T) in MYBPC3 Based on the data reviewed below we consider this a variant of uncertain significance. This variant has been seen in 2 presumably unrelated cases of HCM and a case of infantile DCM. It has also been observed in general population and control samples. No segregation is available. Kabaeva et al (2005) reported this variant in a German male diagnosed with HCM at age 25. Ehlermann et al (2008) reported another German case of HCM with this variant. That patient was a male diagnosed at 46 years of age. These two cases appear to be different cases, given the reported ages of diagnosis. GeneDx reports that p.Thr958Ile was identified in an additional unrelated individual who was diagnosed with DCM in infancy and tested in their lab. I could not find any functional or experimental data on this variant or other variants at this or nearby codons reported in association with disease. In silico analysis with polyphen2 predicts this variant to be benign. The threonine at codon 958 is not conserved across species; it is an isoleucine in chickens, and glutamate in c. elegans. The variant has been seen in 3 of 5154 general population samples. Neither Ehlermann et al (2008) or Kabaeva et al (2005) reported control data. There is no variation listed at this codon in dbSNP or 1000 genomes (as of January 27, 2012). However, the variant was observed in 2 of 3346 Caucasian individuals and 0 of 1608 African Americans in the NHLBI Exome Sequencing Project dataset (as of January 27, 2012). The phenotype of those two individuals is not available, however given the way the samples were accrued, we consider this a general population sample unselected for Mendelian cardiac disease.

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