Submissions for variant NM_000256.3(MYBPC3):c.966G>A (p.Trp322Ter)

dbSNP: rs727503211

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000475261	SCV000198936	pathogenic	Hypertrophic cardiomyopathy	2015-04-14	criteria provided, single submitter	clinical testing	The p.Trp322X variant in MYBPC3 has been reported by our laboratory in two indiv iduals with HCM (childhood-onset in one of them). It has not been identified in large population studies. This nonsense variant leads to a premature termination codon at position 322, which is predicted to lead to a truncated or absent prot ein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon the predicted impact of the variant.
GeneDx	RCV000254919	SCV000321911	pathogenic	not provided	2024-12-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 27532257, 38002985, 37652022, 25611685, 37089884)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475261	SCV000546478	pathogenic	Hypertrophic cardiomyopathy	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp322*) 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: 25611685; internal data). ClinVar contains an entry for this variant (Variation ID: 164136). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000622199	SCV000740175	pathogenic	Cardiovascular phenotype	2024-11-21	criteria provided, single submitter	clinical testing	The p.W322* pathogenic mutation (also known as c.966G>A), located in coding exon 12 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 966. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
All of Us Research Program, National Institutes of Health	RCV000475261	SCV005430052	pathogenic	Hypertrophic cardiomyopathy	2024-07-23	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in individuals with hypertrophic cardiomyopathy or referred for MYBPC3 genetic testing (PMID: 27532257, 25611685, 38002985, 37089884). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000254919	SCV000925155	pathogenic	not provided	2016-12-16	no assertion criteria provided	provider interpretation	p.Trp322X (c.966G>A) in exon 12 of the MYBPC3 gene (NM_000256.3) We have seen this variant in a person with HCM. Testing was performed by Invitae. Truncating variants are an established mechanism of disease for this gene. Therefore, we consider this variant to be very likely disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is weak case data for this variant, which has been seen in at least 2 unrelated cases of HCM (not including this patient's family). The variant has not been reported in the literature. It is also listed on cardiodb.org as present in the cohort of OMGL/LMM HCM cohort, classified as pathogenic. There is no variation at codon 322 listed in the Exome Aggregation Consortium dataset (ExAC; http://exac.broadinstitute.org/), which includes variant calls on ~64,000 unrelated individuals of African, Asian, European, and Latino descent or the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is mean 24x, median 19x, and >90% of people have 10x coverage. The average coverage at that site in gnomAD is median ~25x, mean ~30x, and >90% of people have 10x coverage.