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

gnomAD frequency: 0.00002  dbSNP: rs36211723

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
GeneDx	RCV000788331	SCV000208081	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Published expression studies revealed the absence of mutant transcript and peptide in a myocardial sample from a patient harboring this variant, providing evidence that c.2308 G>A leads to mRNA degradation (Helms et al., 2014); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 33906374, 34097875, 34011823, 31722741, 15519027, 18273486, 18533079, 23054336, 22555271, 16858239, 24111713, 27483260, 24510615, 27532257, 28138913, 28658286, no PMID, 28916354, 28971120, 28771489, 28679633, 29540445, 25351510, 27688314, 26090888, 25740977, 30984009, 31006259, 29997392, 30645170, 31589614, 32746448, 33190526, 25031304)
Invitae	RCV000205565	SCV000261384	pathogenic	Hypertrophic cardiomyopathy	2024-01-17	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 770 of the MYBPC3 protein (p.Asp770Asn). This variant also falls at the last nucleotide of exon 23, which is part of the consensus splice site for this exon. This variant is present in population databases (rs36211723, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15519027, 18273486, 18533079, 22555271, 24111713, 25740977, 28356264). ClinVar contains an entry for this variant (Variation ID: 36604). 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. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 25031304). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000161126	SCV000299245	likely pathogenic	Hypertrophic cardiomyopathy 4	2016-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000252505	SCV000319847	pathogenic	Cardiovascular phenotype	2021-07-19	criteria provided, single submitter	clinical testing	The c.2308G>A pathogenic mutation (also known as p.D770N), located in coding exon 23 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2308. This change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the aspartic acid at codon 770 to asparagine, an amino acid with some highly similar properties. This alteration has been reported in a number of individuals from varying ethnic backgrounds with hypertrophic cardiomyopathy (Van Driest SL et al. J Am Coll Cardiol. 2004;44(9):1903-10; Girolami F et al. J Cardiovasc Med (Hagerstown). 2006;7(8):601-7; Tanjore RR et al. Can J Cardiol. 2008;24(2):127-30; Olivotto I et al. Mayo Clin Proc. 2008;83(6):630-8; Kindel SJ et al. J Card Fail. 2012;18(5):396-403; Miller EM et al. J Genet Couns. 2013;22(2):258-67; Berge KE and Leren TP. Clin Genet. 2014;86(4):355-60). In one study, mutant transcript containing this variant was not detected, indicating this alteration may cause aberrant splicing that could lead to haploinsufficiency (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). In addition, this alteration was suggested to impact calcium handling (Helms AS et al. Circulation. 2016;134(22):1738-1748). This alteration was detected in one control cohort individual; however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000515442	SCV000611209	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804166	SCV000696321	pathogenic	Primary familial hypertrophic cardiomyopathy	2021-12-15	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2308G>A (p.Asp770Asn) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Helms_2014). The variant allele was found at a frequency of 2e-05 in 250492 control chromosomes. c.2308G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. VanDriest_2004, Girolami_2006, Kindel_2012, Berge_2013, Helms_2014). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000161126	SCV000744844	pathogenic	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
Genetics and Genomics Program, Sidra Medicine	RCV000205565	SCV001434094	uncertain significance	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Division of Medical Genetics, University of Washington	RCV000161126	SCV001434289	pathogenic	Hypertrophic cardiomyopathy 4	2020-01-31	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in multiple individuals with hypertrophic cardiomyopathy (Van Driest 2004, Girolami 2006, Tanjore 2008, Olivotto 2008, Kindel 2012, Berge 2014, Calore 2015). This variant has an overall allele frequency of 0.000016 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. This variant has also been reported in the literature to impact splicing (Helms 2014). Thus, this variant is interpreted as pathogenic. PS4-moderate; PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262771	SCV001440761	likely pathogenic	Left ventricular noncompaction 10	2019-01-01	criteria provided, single submitter	clinical testing
KTest Genetics, KTest	RCV001262771	SCV001499965	likely pathogenic	Left ventricular noncompaction 10		criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000161126	SCV003799124	pathogenic	Hypertrophic cardiomyopathy 4	2022-10-17	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PP3
Color Diagnostics, LLC DBA Color Health	RCV003531907	SCV004358683	pathogenic	Cardiomyopathy	2022-12-22	criteria provided, single submitter	clinical testing	This missense variant changes the last nucleotide c.G of exon 23 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 23 splice donor site. A study has shown that both variant transcript and resulting truncated protein were undetectable in myocardial samples from a carrier individual (PMID: 25031304), consistent with the expected degradation of the aberrant transcript by nonsense-mediated RNA decay. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 18273486, 18533079, 23054336, 24111713, 27483260, 27532257, 27688314, 28138913, 28356264, 28658286, 28824454, 28971120, 34137518). This variant has been identified in 4/249118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000161126	SCV000733043	likely pathogenic	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000788331	SCV001918415	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000788331	SCV001957997	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000788331	SCV002034152	pathogenic	not provided		no assertion criteria provided	clinical testing