Submissions for variant NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter)

gnomAD frequency: 0.00001  dbSNP: rs397516037

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168193	SCV000059261	pathogenic	Hypertrophic cardiomyopathy	2011-11-18	criteria provided, single submitter	clinical testing	The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has also been identified in 1/66626 Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs397516037). This nonsense variant leads to a premature term ination codon at position 1233, which is predicted to lead to a truncated or abs ent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets cr iteria to be classified as pathogenic for HCM in an autosomal dominant manner.
GeneDx	RCV000158254	SCV000208189	pathogenic	not provided	2019-11-14	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806)
Invitae	RCV000168193	SCV000218858	pathogenic	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). 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.
Blueprint Genetics	RCV000208463	SCV000264042	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-11-04	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000035610	SCV000292232	likely pathogenic	Hypertrophic cardiomyopathy 4	2015-07-30	criteria provided, single submitter	clinical testing	This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588073	SCV000696331	pathogenic	Cardiovascular phenotype	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000588073	SCV000737358	pathogenic	Cardiovascular phenotype	2021-09-09	criteria provided, single submitter	clinical testing	The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, University of Leuven	RCV000168193	SCV000886773	pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188335	SCV001355372	pathogenic	Cardiomyopathy	2021-05-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295). This variant has been identified in 2/249238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000035610	SCV001428646	pathogenic	Hypertrophic cardiomyopathy 4	2018-07-17	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001270363	SCV001450505	pathogenic	See cases	2020-12-10	criteria provided, single submitter	clinical testing	We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233*) variant to be pathogenic.
Clinical Genetics Laboratory, Region Ostergotland	RCV000035610	SCV001984989	pathogenic	Hypertrophic cardiomyopathy 4	2020-03-24	criteria provided, single submitter	clinical testing	PVS1, PS4, PP5, PP1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001188335	SCV002042207	pathogenic	Cardiomyopathy	2023-04-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000158254	SCV002103237	pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing	PP1, PM2, PS4, PVS1
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000168193	SCV002522188	pathogenic	Hypertrophic cardiomyopathy	2021-08-06	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000168193	SCV002758620	pathogenic	Hypertrophic cardiomyopathy	2022-03-31	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3
Fulgent Genetics, Fulgent Genetics	RCV002482961	SCV002775432	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-08-06	criteria provided, single submitter	clinical testing
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV003390723	SCV004101821	pathogenic	Dilated cardiomyopathy 1I	2023-09-26	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678715	SCV000804884	pathogenic	Left ventricular hypertrophy	2017-08-28	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000158254	SCV001920537	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158254	SCV001952191	pathogenic	not provided		no assertion criteria provided	clinical testing