ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3776del (p.Gln1259fs) (rs727503166)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844679 SCV000198794 pathogenic Left ventricular noncompaction; Hypertrophic cardiomyopathy 2012-09-24 criteria provided, single submitter clinical testing The Gln1259fs variant in MYBPC3 has not been reported in the literature, but has been identified in 3 families with cardiomyopathy tested by our laboratory (Del lefave 2009, LMM unpublished data). In one family, an infant with LVNC and DCM ( likely to be burnt-out HCM) also carried a de novo variant in MYH7, while the af fected mother (LVNC) carried this frameshift variant in isolation (Dellefave 200 9). In a second family, this frameshift variant was observed in isolation in ind ividuals with HCM, though some individuals carried a second likely disease-causi ng variant in MYH7 causing a spectrum of cardiomyopathies to be observed in the family (including HCM, DCM, LVNC, and ARVC; LMM unpublished data). This frameshi ft variant is predicted to alter the protein?s amino acid sequence beginning at position 1259 and lead to a premature termination codon 72 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. H eterozygous loss of function of the MYBPC3 gene is an established disease mechan ism in HCM patients. In summary, this variant meets our criteria to be classifie d as pathogenic (
Ambry Genetics RCV000621300 SCV000737354 pathogenic Cardiovascular phenotype 2019-01-17 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000600560 SCV000745024 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000628841 SCV000749748 pathogenic Hypertrophic cardiomyopathy 2019-09-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MYBPC3 gene (p.Gln1259Argfs*72). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acids of the MYBPC3 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals, a family affected with left ventricular noncompaction or hypertrophic cardiomyopathy (PMID: 20031619, 27532257, 25611685, 20019025, 22115648, 29121657, 19808356). ClinVar contains an entry for this variant (Variation ID: 164021). A different truncation (p.Arg1271*) that lies downstream of this variant has been determined to be pathogenic (PMID: 18533079, 23396983, 27532257). This suggests that deletion of this region of the MYBPC3 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000151057 SCV000901751 likely pathogenic Cardiomyopathy 2017-01-03 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000600560 SCV000733025 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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