Submissions for variant NM_000256.3(MYBPC3):c.3181C>T (p.Gln1061Ter)

gnomAD frequency: 0.00003  dbSNP: rs397516005

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628946	SCV000059213	pathogenic	Hypertrophic cardiomyopathy	2012-07-12	criteria provided, single submitter	clinical testing	The Gln1061X variant in MYBPC3 has been reported in the literature in six HCM pr obands, segregated in 12 affected or clinically suspicious relatives across five families and was absent from 328 healthy control chromosomes (Jaaskelaine 2002, Poutanen 2006). The families were all of Finnish ancestry, and haplotype analys is suggests that this variant could be a founder mutation in this population (Ja askelaine 2002). In addition, this variant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS). Gln1061X is a nonsense variant leading to a premature termination co don at position 1061, 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 HCM patients. In summary, this variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studi es, absence from controls, and established disease mechanism.
Blueprint Genetics	RCV000035563	SCV000188789	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000158219	SCV000208154	pathogenic	not provided	2013-03-18	criteria provided, single submitter	clinical testing	This mutation is dentoed p.Gln1061Stop (CAG>TAG): c.3181 C>T in exon 29 of the MYBPC3 gene (NM_000256.3). The Gln1061Stop mutation in the MYBPC3 gene has been reported in association with HCM (Jaaskelainen P et al., 2002). Jaaskelainen et al. identified Gln1061Stop in 6 unrelated families with HCM from Finland, and it was not observed in 200 control chromosomes. This study reported this mutation co-segregated with HCM in multiple families and suggested Gln1061Stop may be a founder mutation in the Finnish population. Gln1061Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln1061Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Ambry Genetics	RCV000619311	SCV000739930	pathogenic	Cardiovascular phenotype	2023-09-08	criteria provided, single submitter	clinical testing	The p.Q1061* pathogenic mutation (also known as c.3181C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3181. This changes the amino acid from a glutamine to a stop codon within coding exon 29. This is the most prevalent mutation reported to cause hypertrophic cardiomyopathy in the Finnish population and has shown a founder effect (Jääskeläinen P et al. J Mol Med (Berl). 2002;80(7):412-22; Jääskeläinen P et al. Ann Med. 2013;45(1):85-90). 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625352	SCV000745032	pathogenic	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000628946	SCV000749854	pathogenic	Hypertrophic cardiomyopathy	2023-08-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 42690). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12110947, 26267065, 27532257). It is commonly reported in individuals of Finnish ancestry (PMID: 22462493). This variant is present in population databases (rs397516005, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Gln1061*) 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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171135	SCV001333816	pathogenic	Cardiomyopathy	2018-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171135	SCV001348901	pathogenic	Cardiomyopathy	2019-11-25	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 29 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 to segregate with hypertrophic cardiomyopathy in several Finnish families (PMID: 12110947) and is thought to be a founder mutation in the Finnish population (PMID: 22462493, 30775854). This variant has also been reported in several unrelated individuals from other ethnic populations affected with hypertrophic cardiomyopathy (PMID: 19666645, 27532257, 18803133). A study has shown this variant changes the morphology, calcium handling, and electrophysiological properties in cardiomyocytes derived from an individual affected with hypertrophic cardiomyopathy (PMID: 27057166). This variant has been identified in 4/270760 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.
Clinical Genetics, Academic Medical Center	RCV000158219	SCV001924681	pathogenic	not provided		no assertion criteria provided	clinical testing