Submissions for variant NM_000256.3(MYBPC3):c.2670G>A (p.Trp890Ter)

dbSNP: rs397515982

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000197345	SCV000059169	pathogenic	Hypertrophic cardiomyopathy	2017-11-28	criteria provided, single submitter	clinical testing	The p.Trp890X variant in MYBPC3 has been reported in >10 individuals with HCM an d segregated with disease in at least 5 affected relatives (Van Driest 2004, Ehl ermann 2008, LMM data). It was absent from large population studies. This varian t has also been reported by other clinical laboratories in ClinVar (Variation ID 42650). This nonsense variant leads to a premature termination codon at positio n 890, which is predicted to lead to a truncated or absent protein. Heterozygous loss of MYBPC3 function is an established disease mechanism in HCM. In summary, the p.Trp890X variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based on upon segregation studies and the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4, PP1_Moderate.
GeneDx	RCV000158180	SCV000208115	pathogenic	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Identified in a patient with phenotypic features of both HCM and LVNC on cardiac imaging (Goncalves et al., 2022); Not observed in large population cohorts (gnomAD); Expression studies using patient heart tissue suggest that the p.(W890X) transcript is subject to nonsense-mediated mRNA decay (Helms et al., 2014); 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; This variant is associated with the following publications: (PMID: 15519027, 24510615, 25525159, 21415409, 18957093, 22857948, 27532257, 27688314, 25031304, 26265630, 33673806, 34542152, 22112859, 31447099, 35411935)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197345	SCV000253811	pathogenic	Hypertrophic cardiomyopathy	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp890*) 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 individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 15114369, 15519027, 18533079, 18957093, 22857948). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42650). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000158180	SCV000747944	pathogenic	not provided	2016-05-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000197345	SCV001950064	pathogenic	Hypertrophic cardiomyopathy	2021-08-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000158180	SCV002103238	pathogenic	not provided	2021-08-30	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Fulgent Genetics, Fulgent Genetics	RCV002504875	SCV002811062	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147315	SCV003836224	pathogenic	Hypertrophic cardiomyopathy 1	2022-02-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147316	SCV003836309	pathogenic	Left ventricular noncompaction 10	2022-02-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003531910	SCV004358667	pathogenic	Cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 26 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 more than ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 22857948, 24510615, 24793961, 27532257, 33673806, 33495596, 35411935, 35581268) and in two affected individuals in one family (PMID: 18957093). 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.
All of Us Research Program, National Institutes of Health	RCV000197345	SCV004836735	pathogenic	Hypertrophic cardiomyopathy	2023-07-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 26 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 more than ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 22857948, 24510615, 24793961, 27532257, 33673806, 33495596, 35411935, 35581268) and in two affected individuals in one family (PMID: 18957093). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000158180	SCV005199319	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158180	SCV000280242	likely pathogenic	not provided		no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp890Stop (c.3670G>A). Based on the data reviewed below we consider it likely disease causing. In total the variant has been seen in at least 4 unrelated cases with weak segregation data. This variant was initially reported in one individual with HCM by Van Driest S et al (2004) then in two more affected members of one family reported by Ehlermann P et al (2008). The Seidman group report on their program website that they have seen this variant in their cohort (Merk, Seidman et al 2004). Brito et al (2012) observed the variant in one individual in their Portuguese HCM cohort. This is a nonsense variant predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. Many other truncating or null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen in ~6700 published controls and publicly available general population sample. Van Driest et al (2004) report that p.Trp890Stop was not observed in 100 Caucasian and 100 African American presumably healthy individuals. Brito et al (2012) did not observe the variant in 100 control samples. GeneDx did not report internal control data. The variant is not listed in dbSNP or 1000 Genomes. In addition p.Trp890Stop is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of September 2012).
GenomeConnect - Invitae Patient Insights Network	RCV003483449	SCV004228781	not provided	Primary dilated cardiomyopathy; Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-25-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.