Submissions for variant NM_000256.3(MYBPC3):c.3277G>T (p.Gly1093Cys)

gnomAD frequency: 0.00001  dbSNP: rs727503173

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151072	SCV000198813	uncertain significance	not specified	2019-08-02	criteria provided, single submitter	clinical testing	The p.Gly1093Cys variant in MYBPC3 has been identified in 7 individuals with HCM and segregated with disease in 2 affected relatives from 1 family (Burns 2017, Cann 2017, Walsh 2017, LMM data). It has also been identified in 0.008% (8/103250) European chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID#164043). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.
Invitae	RCV000195770	SCV000254437	uncertain significance	Hypertrophic cardiomyopathy	2023-08-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1093 of the MYBPC3 protein (p.Gly1093Cys). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 164043). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27000522, 27532257, 28790153, 33782553). 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.
Blueprint Genetics	RCV000788379	SCV000927465	uncertain significance	not provided	2017-11-09	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000195770	SCV000996353	uncertain significance	Hypertrophic cardiomyopathy	2017-04-19	criteria provided, single submitter	research	The MYBPC3 Gly1093Cys variant has not been reported previously in literature, however it has been seen in 2 HCM cases in one laboratory (LMM Clinvar: SCV000198813.2, personal communication) and another 3 HCM cases by Oxford Medical Genetics Laboratories (Walsh R, et al., 2017), the variant was also identified in an affected family member (personal communications). The variant is absent in the large Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the 1000 genomes project (http://www.1000genomes.org/). We identified this variant in a HCM proband with no family history of disease. Computational tools SIFT, PolyPhen-2, and MutationTaster all predict this variant to have a deleterious effect, but no prediction is called by PolyPhen-HCM. In summary, based on rarity in the general population, reports of a few HCM probands carrying the variant and in silico tools supportive of a deleterious effect on the protein, we classify MYBPC3 Gly1093Cys as a variant of "uncertain significance".
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171132	SCV001333813	uncertain significance	Cardiomyopathy	2022-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171132	SCV001355384	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 1093 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28790153, 33495597). It has also been reported in an individual affected with sudden unexplained death and cardiomyopathy identified on autopsy (PMID: 27000522). Two of eight carriers from this family were clinically affected. This variant has been identified in 9/233948 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000788379	SCV001788700	uncertain significance	not provided	2019-02-18	criteria provided, single submitter	clinical testing	Reported in association with HCM (Cann et al., 2016; Burns et al., 2017; Ingles et al., 2017; Walsh et al., 2017). Cann et al. (2016) identified G1093C in a proband with sudden death immediately after exercise who was diagnosed with HCM at autopsy; segregation analysis and clinical evaluation revealed that out of the eight relatives who also harbored G1093C, two were clinically affected with HCM.; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 164043; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28790153, 27000522, 28408708, 27532257)
Ambry Genetics	RCV002444617	SCV002612081	uncertain significance	Cardiovascular phenotype	2023-06-14	criteria provided, single submitter	clinical testing	The p.G1093C variant (also known as c.3277G>T), located in coding exon 30 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3277. The glycine at codon 1093 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in clinical hypertrophic cardiomyopathy (HCM) and HCM genetic testing cohorts and was reported to segregate with disease in one small family; however, details were limited (Burns C et al, Circ Cardiovasc Genet. 2017 Aug;10:; Cann F et al, Clin Genet. 2017 01;91:22-29; Walsh R et al, Genet Med. 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.