Submissions for variant NM_000256.3(MYBPC3):c.2893C>T (p.Gln965Ter)

dbSNP: rs730880578

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158193	SCV000208128	pathogenic	not provided	2013-05-10	criteria provided, single submitter	clinical testing	This mutation is denoted p.Gln965Stop (CAG>TAG): c.2893 C>T in exon 27 of the MYBPC3 gene (NM_000256.3). The Gln965Stop mutation in the MYBPC3 gene has been reported in a proband with HCM and 5 asymptomatic family members (Christaanson I et al., 2010). However, Gln965Stop 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 addition, Gln965Stop was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Gln965Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Invitae	RCV001850208	SCV002170478	pathogenic	Hypertrophic cardiomyopathy	2023-08-02	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: 180986). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22115648). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln965*) 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).
Revvity Omics, Revvity	RCV000158193	SCV003823578	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV003388831	SCV004099298	pathogenic	Hypertrophic cardiomyopathy 4	2023-10-06	criteria provided, single submitter	clinical testing	Heterozygous variant NM_000256.3:c.2893C>T (p.Gln965*) in the MYBPC3 gene was found on WES data in female proband (36 y.o., Caucasian) with hypertrophic cardiomyopathy. Additional rare candidate variant NM_002471.4:c.5660C>T (p.Ala1887Val) (Class III of pathogenicity) in gene MYH6 was found in this proband. This variant is absent in The Genome Aggregation Database (gnomAD) v2.1.1 and v.3.1.2 (Date of access with 06-10-2023). Clinvar contains an entry for this variant (Variation ID: 180986). This variant has been reported in 3 publications in patients with variable phenotypes. Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Pathogenic with following criteria selected: PVS1, PS4_Supporting, PM2, (PP5).