Submissions for variant NM_000256.3(MYBPC3):c.1235_1236del (p.Ile411_Phe412insTer)

dbSNP: rs397515894

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168331	SCV000059027	pathogenic	Hypertrophic cardiomyopathy	2017-02-02	criteria provided, single submitter	clinical testing	The p.Phe412X variant has been reported in 3 individuals with HCM (Richard 2003, Van Driest 2004, LMM data). This variant was absent from large population studi es. This variant is a deletion of 2 bases resulting in a premature termination c odon at position 412, which is predicted to lead to a truncated or absent protei n. Heterozygous loss of function of the MYBPC3 gene is an established disease me chanism in individuals with HCM. This variant has been reported in ClinVar (Vari ant ID: 42514). In summary, this variant meets our criteria to be classified as pathogenic based on the predicted impact of the variant.
GeneDx	RCV000158344	SCV000208279	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Identified in multiple patients with HCM referred to GeneDx and in published literature (Richard et al., 2003; Van Driest et al., 2004; Ehlermann et al., 2008; Berge et al., 2014; Kapplinger et al., 2014; Viswanathan et al., 2017); of note, this variant is also described as del TT[10512-10513] and I411 fs/0; 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; Not observed in large population cohorts (gnomAD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42514; ClinVar); This variant is associated with the following publications: (PMID: 24111713, 24510615, 12707239, 18957093, 15519027, 29121657, 35653365)
Invitae	RCV000168331	SCV000219019	pathogenic	Hypertrophic cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe412*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 18957093, 24111713, 24510615). ClinVar contains an entry for this variant (Variation ID: 42514). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587876	SCV000696311	pathogenic	Cardiovascular phenotype	2016-05-04	criteria provided, single submitter	clinical testing	Variant summary: The MYBPC3 c.1235_1236delTT (p.Phe412Terfs) variant is a frameshift mutation predicted to cause loss of normal protein function due to production of a truncated protein or by the absence of the protein product due to nonsense-mediated mRNA decay. Mutation taster predicts a damaging outcome for this variant. It was not found in 102952 control chromosomes while it was reported in several patients with HCM from the literature. In one family, the variant co-segregated with disease, indicating pathogenicity. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu667fs), further supporting a deleterious outcome. In addition, clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic.
Ambry Genetics	RCV000587876	SCV000736945	pathogenic	Cardiovascular phenotype	2023-08-23	criteria provided, single submitter	clinical testing	The c.1235_1236delTT pathogenic mutation, located in coding exon 15 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 1235 to 1236, causing a translational frameshift with a predicted alternate stop codon (p.F412*). This alteration, also referred to as del TT[10512-10513] or I411 fs/0, has been reported in individuals with hypertrophic cardiomyopathy (Richard P et al. Circulation, 2003 May;107:2227-32; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10). 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.
Blueprint Genetics	RCV000158344	SCV000928149	pathogenic	not provided	2018-12-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000158344	SCV001249487	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001525513	SCV001735649	pathogenic	Cardiomyopathy	2020-10-13	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 15 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals and in a family affected with hypertrophic cardiomyopathy or referred for hypertrophic cardiomyopathy genetic testing (PMID: 12707239, 18957093, 24111713, 24510615). This variant has not been identified 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.