ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2048G>A (p.Trp683Ter)

dbSNP: rs397515942
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000805978 SCV000059107 pathogenic Hypertrophic cardiomyopathy 2011-12-09 criteria provided, single submitter clinical testing The Trp683X variant has been reported in 1 individual with HCM and was absent fr om 200 control chromosomes (Richard 2003). This variant leads to a premature sto p at codon 683. This alteration is predicted to lead to a truncated or absent pr otein. Loss of function of the MYBPC3 gene is an established disease mechanism i n HCM patients, which makes it highly likely that the Trp683X variant is pathoge nic.
Invitae RCV000805978 SCV000945955 pathogenic Hypertrophic cardiomyopathy 2020-11-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 27532257, 25228707). ClinVar contains an entry for this variant (Variation ID: 42591). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp683*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223849 SCV000280231 likely pathogenic not provided 2012-01-18 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.Trp683X ( c.2048G>A) in MYBPC3 Given the strong evidence that nonsense variants in MYBPC3 cause HCM, we consider this variant likely disease-causing, with sufficient confidence to use it for predictive genetic testing in the family. The variant has been seen in at least one case of HCM (not including the patient's family). There is no segregation data available. Richard et al (2003) reported the variant in a patient with HCM from their French cohort. Nonsense variants in the MYBPC3 gene are a frequent cause of HCM (ex. p.Gln76Stop, p.Tyr79Stop, p.Gly115Stop, p.Pro161Stop, p.Gln425Stop) as are splicing and frameshift variants (see http://genepath.med.harvard.edu, www.biobaseinternational.com/pages). In total the variant has not been seen in ~6000 published controls and publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6000 Caucasian and African American individuals (as of 6/20/2012). Of note, there is only one frameshift or nonsense variant listed in that entire cohort. The variant was not observed in the following published control samples: 100 (Richard et al 2003).

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