Submissions for variant NM_000256.3(MYBPC3):c.1090+1G>T

dbSNP: rs727504269

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000288163	SCV000329718	pathogenic	not provided	2018-02-12	criteria provided, single submitter	clinical testing	The c.1090+1 G>T pathogenic variant in the MYBPC3 gene has been reported in multiple individuals in association with HCM (Sato et al., 2012; Otsuka et al., 2012; Murphy et al., 2016; Walsh et al., 2017). Sato et al. (2012) observed this variant (reported as IVS11+1 G>T due to alternative nomenclature) in a Japanese female who was diagnosed with HCM at 17 years-old and developed dilated phase HCM at 61 years-old. This patient also harbored another variant in the MYBPC3 gene, reportedly located in trans, which may also have contributed to her phenotype (Sato et al., 2012). Additionally, the c.1090+1 G>T variant has also been observed in other individuals referred for cardiomyopathy genetic testing at GeneDx. This variant destroys the canonical splice donor site in intron 12 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Furthermore, two different variants involving the same nucleotide (c.1090+1 G>A, c.1090+1 G>C) have each been reported in association with HCM (Girolami et al., 2006; Millat et al., 2010), and several other downstream splice site variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Finally, the c.1090+1 G>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211796	SCV001214522	pathogenic	Hypertrophic cardiomyopathy	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs727504269, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16858239, 20624503, 22112859, 26914223, 27532257; internal data). This variant is also known as IVS11+1G>T. ClinVar contains an entry for this variant (Variation ID: 177686). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798496	SCV002042116	pathogenic	Cardiomyopathy	2020-09-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211796	SCV000203944	pathogenic	Hypertrophic cardiomyopathy	2013-03-04	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory