ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1510_1512AAG[1] (p.Lys505del) (rs727504287)

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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 RCV000154300 SCV000203959 uncertain significance not specified 2019-08-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys505del variant in MYBPC3 has been reported in 10 heterozygous individuals with HCM, 1 individual with SCD, and 1 individual with severe early-onset left ventricular noncompaction, who carried a second pathogenic variant in MYBPC3 (Cardim 2005, Mademont-Soler 2017, Marsiglia 2013, Richard 2003, Rodriguez-Garcia 2010, Schaefer 2014, Sabater-Molina 2013, Campuzano 2017, Ambry pers. comm., Invitae pers. comm., LMM data). Additionally, it segregated with disease in 2 affected individuals from 2 families (Mademont-Soler 2017, Rodriguez-Garcia 2010). It has also been identified in 1/35360 Latino chromosomes and 2/128444 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 505 and is not predicted to alter the protein reading-frame; it is unclear if this deletion will impact the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Lys505del variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2, PM4_Supporting.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201476 SCV000256175 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Invitae RCV000536227 SCV000623529 uncertain significance Hypertrophic cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing This variant, c.1513_1515delAAG, results in the deletion of 1 amino acid of the MYBPC3 protein (p.Lys505del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 16566405, 24093860, 27532257, 12707239, 28138913, 20433692), an individual with sudden cardiac death (PMID: 28255936), and in an individual with severe left ventricular hypertrophy who carried another pathogenic variant in MYBPC3 (PMID: 24602869). This variant is also described as Del [10957-10959], Del K504 in the literature (PMID: 12707239). ClinVar contains an entry for this variant (Variation ID: 177699). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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.
Ambry Genetics RCV000620866 SCV000740257 uncertain significance Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770364 SCV000901805 uncertain significance Cardiomyopathy 2016-02-23 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000536227 SCV000995124 likely pathogenic Hypertrophic cardiomyopathy 2018-12-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256770 SCV001433214 likely pathogenic Familial hypertrophic cardiomyopathy 1 2020-02-20 criteria provided, single submitter clinical testing

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