ClinVar Genomic variation as it relates to human health

Not observed 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: 29095814)

This sequence change creates a premature translational stop signal (p.Gln339*) 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 dilated cardiomyopathy (PMID: 29095814). ClinVar contains an entry for this variant (Variation ID: 181056). For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 12 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 one individual affected with hypertrophic cardiomyopathy (PMID: 30297972, 32841044). It has also been reported to occur de novo in one individual affected with dilated cardiomyopathy (PMID: 29095814). 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.

The p.Q339* pathogenic mutation (also known as c.1015C>T), located in coding exon 12 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1015. This changes the amino acid from a glutamine to a stop codon within coding exon 12. 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.

The MYBPC3 c.1015C>T variant is predicted to result in premature protein termination (p.Gln339*). This variant was reported to occur de novo in an individual with dilated cardiomyopathy (Table S2. Hu et al. 2018. PubMed ID: 29095814). This variant was also reported as pathogenic in the de novo and heterozygous states in two individuals with hypertrophic cardiomyopathy (Table S1. Stava et al. 2022. PubMed ID: 35653365; Supplemental Table 1. Ho et al. 2018. PubMed ID: 30297972). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181056/). Nonsense variants in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic.

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. MYBPC3 p.Gln339Stop Given the strong evidence that nonsense variants in MYBPC3 cause HCM, we consider this variant likely disease-causing. The variant has been seen in at least one case of HCM. This is a nonsense variant predicted to cause either a truncated protein or complete absence of the protein due to nonsense mediated mRNA decay. Nonsense variants in the MYBPC3 gene are a frequent cause of HCM (p.Gln76Stop, p.Tyr79Stop, p.Gly115Stop, p.Pro161Stop, p.Gln425Stop) as are splicing and frameshift variants (see http://genepath.med.harvard.edu, www.biobaseinternational.com/pages). There is also a nearby nonsense variant (Tyr340Stop) associated with HCM. Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). Based on the predicted functional effect on the resulting protein this variant is likely associated with disease. In total the variant has not been seen in ~6500 published controls and publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of 6/19/2013). Of note, there are only four frameshift or nonsense variants listed in that entire cohort at this time. The variant is not listed in dbSNP or 1000 Genomes (as of 6/19/2013).