Submissions for variant NM_000256.3(MYBPC3):c.2148+1G>T

dbSNP: rs1060499604

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000702923	SCV000731715	likely pathogenic	Hypertrophic cardiomyopathy	2017-11-03	criteria provided, single submitter	clinical testing	The c.2148+1G>T variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy or in large population studies but has been reported by ot her clinical laboratories in ClinVar (Variation ID 417931). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predi cted to cause altered splicing leading to an abnormal or absent protein. Heteroz ygous loss of function of the MYBPC3 gene is an established disease mechanism in hypertrophic cardiomyopathy (HCM). In summary, although additional studies are required to fully establish its clinical significance, the c.2148+1G>T variant i s likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Ambry Genetics	RCV000619126	SCV000736411	likely pathogenic	Cardiovascular phenotype	2018-05-29	criteria provided, single submitter	clinical testing	The c.2148+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 22 of the MYBPC3 gene. This alteration has been reported as a secondary cardiac finding in an exome cohort (Al-Shamsi A et al. Orphanet J Rare Dis, 2016 Jul;11:94). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae	RCV000702923	SCV000831800	likely pathogenic	Hypertrophic cardiomyopathy	2018-05-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 22 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 417931). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001569200	SCV001793233	likely pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing	Has not been previously published in association with MYBPC3-related disorders to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 31447099, 27391121, 26582918)
Color Diagnostics, LLC DBA Color Health	RCV001805094	SCV002052230	likely pathogenic	Cardiomyopathy	2021-07-26	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +1 position of intron 22 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for genetic testing (PMID: 27391121). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV001569200	SCV002502886	likely pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000702923	SCV004831706	likely pathogenic	Hypertrophic cardiomyopathy	2023-11-06	criteria provided, single submitter	clinical testing	The c.2148+1G>A variant of the MYBPC3 gene disrupts the splicing donor site in intron 22 and is expected to alter RNA splicing, leading to disrupted protein structure and function. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. Also, this variant is absent in the general population by the gnomAD database. Based on these evidence, c.2148+1G>A variant of the MYBPC3 gene is classified as likely pathogenic.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477839	SCV000536878	likely pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2015-10-03	no assertion criteria provided	research