Submissions for variant NM_000256.3(MYBPC3):c.2179G>A (p.Val727Met)

gnomAD frequency: 0.00004  dbSNP: rs564378953

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158140	SCV000208075	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Identified independently and in conjunction with additional cardiogenetic variants in individuals with cardiomyopathy in published literature (Lopes et al., 2015; Burns et al., 2017; Helmes et al., 2020) and in individuals referred for cardiomyopathy genetic testing at GeneDx, but segregation data is limited or absent at this time; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24755471, 25351510, 32841044, 28790153, 31376648)
Ambry Genetics	RCV000621359	SCV000736873	uncertain significance	Cardiovascular phenotype	2022-06-03	criteria provided, single submitter	clinical testing	The p.V727M variant (also known as c.2179G>A), located in coding exon 23 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2179. The valine at codon 727 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405). This alteration was also described in an HCM patient who had a second alteration in MYBPC3; however, the phase was unknown (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:). This alteration was also reported in a suspected drug-induced arrhythmia/sudden unexplained death cohort (Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000628990	SCV000749900	uncertain significance	Hypertrophic cardiomyopathy	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 727 of the MYBPC3 protein (p.Val727Met). This variant is present in population databases (rs564378953, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 28790153). This missense change has been observed to co-occur in individuals with a different variant in MYBPC3 that has been determined to be pathogenic (PMID: 25351510, 28790153), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 180964). 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. 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.
Blueprint Genetics	RCV000158140	SCV000927374	uncertain significance	not provided	2017-08-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180077	SCV001344931	uncertain significance	Cardiomyopathy	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 727 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 25351510, 28790153, 32841044). One of these individuals also carried a different pathogenic missense variant in the same gene (PMID: 28790153). This variant has been identified in 19/279250 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000158140	SCV001963079	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158140	SCV001964165	uncertain significance	not provided		no assertion criteria provided	clinical testing