Submissions for variant NM_000256.3(MYBPC3):c.3404ACT[1] (p.Tyr1136del)

dbSNP: rs730880674

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766373	SCV000208337	uncertain significance	not provided	2017-03-21	criteria provided, single submitter	clinical testing	The c.3407_3409delACT variant of uncertain significance in the MYBPC3 gene has been reported previously in two individuals with HCM; however, no detailed clinical or segregation data were provided (Sequeira et al., 2013; Murphy et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This three nucleotide deletion results in elimination of a tyrosine residue at position 1136, and does not result in a shift in reading frame. Tyrosine at this position is conserved in mammals and in silio analysis predicts this deletion to be damaging to the protein structer/function. However, the c.3407_3409delACT variant lacks sufficient evidence, including observation in a significant number of affected inidividuals, segregation studies, and functional characterization, that would further clarify its potential pathogenicity.
Blueprint Genetics	RCV000208115	SCV000264060	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2015-10-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625071	SCV000743674	pathogenic	Hypertrophic cardiomyopathy 4	2017-10-26	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625071	SCV000745028	pathogenic	Hypertrophic cardiomyopathy 4	2017-05-31	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000158402	SCV000748030	uncertain significance	not specified	2017-06-12	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000768480	SCV000886771	likely pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769307	SCV000900685	likely pathogenic	Cardiomyopathy	2023-04-21	criteria provided, single submitter	clinical testing
Invitae	RCV000768480	SCV000949788	likely pathogenic	Hypertrophic cardiomyopathy	2023-06-13	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 181102). This variant has been observed in individuals with hypertrophic cardiomyopathy and/or MYBPC3-related conditions (PMID: 23508784, 26914223, 30685992, 31513939, 33673806; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.3407_3409del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Tyr1136del), but otherwise preserves the integrity of the reading frame.
Clinical Genetics Laboratory, Region Ostergotland	RCV000625071	SCV002056147	likely pathogenic	Hypertrophic cardiomyopathy 4	2021-02-24	criteria provided, single submitter	clinical testing	PS4, PM2, PM4
Ambry Genetics	RCV002453544	SCV002612721	likely pathogenic	Cardiovascular phenotype	2023-11-27	criteria provided, single submitter	clinical testing	The c.3407_3409delACT variant (also known as p.Y1136del) is located in coding exon 31 of the MYBPC3 gene. This variant results from an in-frame ACT deletion at nucleotide positions 3407 to 3409. This results in the in-frame deletion of a tyrosine at codon 1136. This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Lopes LR et al. J Med Genet, 2013 Apr;50:228-39; Sequeira V et al. Circ. Res., 2013 May;112:1491-505; Witjas-Paalberends ER et al. Cardiovasc. Res., 2014 Jul;103:248-57; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Dorsch LM et al. Cells, 2019 07;8:[ePub ahead of print]; Mazzarotto F et al. Genet Med, 2019 02;21:284-292; Nagyova E et al. Bratisl Lek Listy, 2019 Oct;120:46-51; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Harper AR et al. Nat Genet, 2021 02;53:135-142; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126; Tadros R et al. Nat Genet, 2021 02;53:128-134; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003147372	SCV003835956	likely pathogenic	Left ventricular noncompaction 10	2022-12-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000625071	SCV003836065	likely pathogenic	Hypertrophic cardiomyopathy 4	2022-12-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000625071	SCV004045788	likely pathogenic	Hypertrophic cardiomyopathy 4	2023-04-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000768480	SCV004825087	likely pathogenic	Hypertrophic cardiomyopathy	2023-11-13	criteria provided, single submitter	clinical testing	The c.3407_3409del (p.Tyr1136del) variant of the MYBPC3 gene leads to the deletion of 1 amino acid of the MYBPC3 protein (p.Tyr1136del), but otherwise preserves the integrity of the reading frame. This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24835277, 31323898, 29875424, 23508784, 33495596, 26914223, 30685992, 31513939, 33673806). This variant is not present in the general population by the Genome Aggregation Database (gnomAD). Therefore the c.3407_3409del (p.Tyr1136del) variant of the MYBPC3 gene is classified as likely pathogenic.
Institute of Human Genetics, Medical University Innsbruck	RCV004555539	SCV005044712	likely pathogenic	Brugada syndrome		criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766373	SCV001740806	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766373	SCV001921352	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766373	SCV001958458	pathogenic	not provided		no assertion criteria provided	clinical testing