Submissions for variant NM_000256.3(MYBPC3):c.3286G>T (p.Glu1096Ter)

gnomAD frequency: 0.00001  dbSNP: rs121909377

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628863	SCV000059223	pathogenic	Hypertrophic cardiomyopathy	2018-07-03	criteria provided, single submitter	clinical testing	The p.Glu1096X variant in MYBPC3 has been reported in 7 individuals with HCM, in cluding 1 individual with HCM who also carries a variant in MYH7 (Richard 1999, Richard 2003, Marsiglia 2013, Walsh 2016, LMM data). The p.Glu1096X variant was observed in isolation in 3 affected relatives (including an obligate carrier) an d in combination with the MYH7 variant in 1 affected relative. The proband and t he relative, who both carry the MYH7 and this variant, exhibited more severe dis ease compared with the other affected relatives. This variant has been identifie d in 1/11,964 African chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/; dbSNP rs121909377). This nonsense variant leads to a premature termination codon at position 1096, which is predicted to lead t o a truncated or absent protein. In summary, this variant meets criteria to be c lassified as pathogenic for HCM in an autosomal dominant manner based upon the p redicted impact of the variant, segregation studies, and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1.
GeneDx	RCV000158223	SCV000208158	pathogenic	not provided	2023-03-16	criteria provided, single submitter	clinical testing	Found independently in three affected individuals from a French Caribbean family with HCM, including an obligate carrier, and co-occurred with a missense variant in the MYH7 gene in two affected relatives with more severe disease (Richard et al., 1999); 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: 28193612, 10424815, 12707239, 24093860, 27532257, 12601548, 31447099, 18761664, 20031583, 31513939, 32009526, 34542152)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000009147	SCV000256169	likely pathogenic	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621059	SCV000740203	pathogenic	Cardiovascular phenotype	2022-03-03	criteria provided, single submitter	clinical testing	The p.E1096* pathogenic mutation (also known as c.3286G>T), located in coding exon 30 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3286. This changes the amino acid from a glutamic acid to a stop codon within coding exon 30. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (Richard P et al. J. Med. Genet., 1999 Jul;36:542-5; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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.
Invitae	RCV000628863	SCV000749771	pathogenic	Hypertrophic cardiomyopathy	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1096*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10424815, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8616). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000009147	SCV000840019	pathogenic	Hypertrophic cardiomyopathy 4	2018-04-25	criteria provided, single submitter	clinical testing	This c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene has been reported in multiple hypertrophic cardiomyopathy (HMC) patients [PMID: 7786104, 10424815, 12707239] while observed with extremely low allele frequency in general population according to gnomad database. It has been demonstrated that this variant was co-segregated with disease in a HCM family [PMID: 10424815]. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene is classified as pathogenic.
Center for Human Genetics, University of Leuven	RCV000628863	SCV000886769	pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496311	SCV002807190	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486544	SCV004239377	pathogenic	Cardiomyopathy	2022-07-08	criteria provided, single submitter	clinical testing
OMIM	RCV000009147	SCV000029364	pathogenic	Hypertrophic cardiomyopathy 4	1999-07-01	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000158223	SCV000809464	pathogenic	not provided	2018-09-16	no assertion criteria provided	research