ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.223G>A (p.Asp75Asn) (rs375471260)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201432 SCV000256165 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
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 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 75 of the MYBPC3 protein (p.Asp75Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs375471260, ExAC 0.02%). This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 21943931, 27600940, 21488259) and in a family with suggestive electrocardiographic alterations but no diagnoses of HCM. ClinVar contains an entry for this variant (Variation ID: 161313). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Color RCV001181801 SCV001347029 uncertain significance Cardiomyopathy 2019-12-02 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148688 SCV000190415 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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