ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2308G>A (p.Asp770Asn) (rs36211723)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000205565 SCV000059128 pathogenic Hypertrophic cardiomyopathy 2018-06-27 criteria provided, single submitter clinical testing The p.Asp770Asn variant in MYBPC3 has been reported in >15 individuals with HCM and segregated with disease in one affected relative (Helms 2014, Girolami 2006, McNamara 2017, Olivotto 2008, Tanjore 2008, Van Driest 2004, Walsh 2016, LMM da ta, GeneDx pers comm). It has also been identified in 4/246120 chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP r s36211723). This variant is located in the last base of exon 23, which is part o f the 5? splice region and computational tools predict an impact on splicing. Ex amination of cardiac tissue from a patient with HCM who carried this variant sho wed a severe impact on splicing leading to nonsense mediated decay (Helms 2014). Heterozygous loss of function of the MYBPC3 gene is an established disease mech anism in individuals with HCM. In summary, this variant meets criteria to be cla ssified as pathogenic for HCM in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PS3, PM2.
Invitae RCV000205565 SCV000261384 pathogenic Hypertrophic cardiomyopathy 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 770 of the MYBPC3 protein (p.Asp770Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. It also falls at the last nucleotide of exon 23 of the MYBPC3 mRNA. This variant is present in population databases (rs36211723, ExAC <0.01%). This variant has been reported in many individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15519027, 16858239, 18273486, 18533079, 22555271, 24111713, 25740977). ClinVar contains an entry for this variant (Variation ID: 36604). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Supporting this notion, experimental studies have shown that this variant leads to an aberrant MYBPC3 mRNA processing (PMID: 25031304). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000161126 SCV000299245 likely pathogenic Familial hypertrophic cardiomyopathy 4 2016-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000252505 SCV000319847 pathogenic Cardiovascular phenotype 2018-06-18 criteria provided, single submitter clinical testing Last nucleotide of exon;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification
Fulgent Genetics,Fulgent Genetics RCV000515442 SCV000611209 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000252505 SCV000696321 pathogenic Cardiovascular phenotype 2016-01-14 criteria provided, single submitter clinical testing Variant summary: Variant of interest affects a conserved nucleotide and results in a replacement of an Aspartic acid (D) with a Asparagine (N). 5/5 in silico tools predict deleterious outcome along with 3/5 in silico tools via Alamut predicting the elimination of a splice donor site for this substitution. These prediction were confirmed by Helms et al_2014 demonstrating the variant to result in the loss of the mutant transcript leading to haploinsufficiency, a known mechanism of HCM. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease casing MYBPC3 variant (0.1%) while it was observed in several HCM patients indicating a deleterious impact. Furthermore, clinical diagnostic laboratories classify variant as Likely Pathogenic/Pathgoenic" via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as a Pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000161126 SCV000744844 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000788331 SCV000927399 pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845356 SCV000987409 pathogenic Conduction disorder of the heart criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000161126 SCV000733043 likely pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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