Submissions for variant NM_000256.3(MYBPC3):c.613C>T (p.Gln205Ter)

dbSNP: rs397516061

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035650	SCV000059301	pathogenic	Hypertrophic cardiomyopathy	2019-03-07	criteria provided, single submitter	clinical testing	The p.Gln205X variant in MYBPC3 has been identified in 1 individual with HCM (Alfares 2015) and 1 individual with HCM and ventricular tachycardia (Lu 2018). It was absent from large population studies. This variant has been reported in ClinVar (Variation ID:42774). This nonsense variant leads to a premature termination codon at position 205, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant hypertrophic cardiomyopathy. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon its predicted loss of function impact, identification in affected individuals and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2.
GeneDx	RCV000158466	SCV000208401	pathogenic	not provided	2022-08-01	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: 28408708, 27532257, 25611685, 25351510, 31424582, 30681346, 28569743, 30165862)
Invitae	RCV000035650	SCV002245510	pathogenic	Hypertrophic cardiomyopathy	2022-10-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42774). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 30165862). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln205*) 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).
Ambry Genetics	RCV003298050	SCV003989418	pathogenic	Cardiovascular phenotype	2023-06-02	criteria provided, single submitter	clinical testing	The p.Q205* variant (also known as c.613C>T), located in coding exon 5 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 613. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been reported in multiple hypertrophic cardiomyopathy (HCM) cohorts, although clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Lu C et al. J Transl Med, 2018 08;16:241). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000035650	SCV001430860	pathogenic	Hypertrophic cardiomyopathy	2019-12-10	no assertion criteria provided	research	The MYBPC3 Gln205Ter variant has been reported in 2 HCM probands. It is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in 1 HCM proband and one affected family member (Ingles et al., 2017). Computational tools CADD and MutationTaster indicate a likely deleterious role. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in >2 HCM proband (PS4_supporting) and is rare in the general population (PM2), therefore we classify MYBPC3 Gln205Ter as "pathogenic".