ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.223G>A (p.Asp75Asn)

gnomAD frequency: 0.00003  dbSNP: rs375471260
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154385 SCV000204051 uncertain significance not specified 2019-07-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp75Asn variant in MYBCP3 has been reported in 6 individuals with HCM and 1 individual with DCM (Rodriguez-Garcia 2010, Lakdawala 20111, Cecconi 2016, Mademont-Soler 2017, Walsh 2017, Wiffin 207, Sousa 2019). One individual with HCM carried an additional pathogenic variant in MYBPC3 (Mademont-Soler 2017). It has also been identified in 4/100946 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3.
Center for Human Genetics, University of Leuven RCV000497441 SCV000579535 uncertain significance Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score unknown significance
Invitae RCV000497441 SCV000623549 uncertain significance Hypertrophic cardiomyopathy 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 75 of the MYBPC3 protein (p.Asp75Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 21488259, 21943931, 27600940, 28771489, 30871747, 31513939). ClinVar contains an entry for this variant (Variation ID: 161313). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000201432 SCV001138323 uncertain significance Hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001181801 SCV001347029 uncertain significance Cardiomyopathy 2022-09-30 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 75 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 27600940, 31513939), as well as in a healthy control subject (PMID: 20433692). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has been identified in 4/228528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV001576359 SCV001803525 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing Reported in association with HCM, though many publications did not include patient-specific clinical details (Harris et al., 2011; Lakdawala et al., 2011; Andreasen et al., 2013; Amendola et al., 2015; Ho et al., 2015; Cecconi et al., 2016; Ito et al., 2017; Walsh et al., 2017); Reported in a 12-year-old Spanish female with HCM who also harbored a pathogenic MYBPC3 splice site variant (Mademont-Soler et al., 2017); Segregation studies in a family with HCM revealed this variant in one possibly affected family member and one family member with a normal phenotype, whereas the variant was absent in a family member with suggestive electrocardiographic alterations (Rodriguez-Garcia et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31513939, 30871747, 23299917, 25637381, 21488259, 27532257, 21943931, 28679633, 28771489, 27600940, 25543971, 21415409, 28518168)
CSER _CC_NCGL, University of Washington RCV000148688 SCV000190415 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201432 SCV000256165 likely pathogenic Hypertrophic cardiomyopathy 4 flagged submission clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.