Submissions for variant NM_000256.3(MYBPC3):c.2274C>T (p.Gly758=)

gnomAD frequency: 0.00001  dbSNP: rs397515957

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000701621	SCV000830431	uncertain significance	Hypertrophic cardiomyopathy	2022-07-05	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant results in the activation of a cryptic splice site in exon 23 (PMID: 30025578). ClinVar contains an entry for this variant (Variation ID: 42609). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30025578). This variant is present in population databases (rs397515957, gnomAD no frequency). This sequence change affects codon 758 of the MYBPC3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 12 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
GeneDx	RCV001642553	SCV001858605	likely pathogenic	not provided	2023-04-13	criteria provided, single submitter	clinical testing	RNA analysis revealed exon 23 was truncated by 36 nucleotides, leading to an in-frame deletion of 12 amino acids (Gly758-Ile769) (Bagnall et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing.; Reported in ClinVar with conflicting classifications (ClinVar Variant ID# 42609; ClinVar); This variant is associated with the following publications: (PMID: 31243064, 30025578)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035477	SCV000059125	likely benign	not specified	2008-03-01	flagged submission	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000701621	SCV001430835	likely pathogenic	Hypertrophic cardiomyopathy	2019-05-08	no assertion criteria provided	research	MYBPC3 Gly758= has been previously reported in a HCM proband by another laboratory (LMM, ClinVar:SCV000059125) and is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband, and other affected relatives (Bagnall et al., 2018). Splice prediction tool MaxEntScan predicts that this variant will result in aberrant splicing. RNA extracted from the blood of all 3 affected individuals showed that this causes a new splice donor and aberrant splicing of exon 23, resulting in a 36 base pair in-frame truncation (Bagnall et al., 2018). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is rare in the general population (PM2), causes a truncated protein (PM4), segregates to affected family members (PP1) and in silico tools predict aberrant splicing to occur (PP3), therefore we classify MYBPC3 Gly758= as 'likely pathogenic'.