Submissions for variant NM_000256.3(MYBPC3):c.3154A>G (p.Met1052Val)

gnomAD frequency: 0.00003  dbSNP: rs730880589

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158218	SCV000208153	uncertain significance	not provided	2019-10-16	criteria provided, single submitter	clinical testing	Reported in a patient referred for DCM genetic testing; however, additional clinical information was not provided (Walsh et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171136	SCV001333817	uncertain significance	Cardiomyopathy	2020-03-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171136	SCV001352613	uncertain significance	Cardiomyopathy	2023-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1052 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 an individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 11/272206 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.
Invitae	RCV001209565	SCV001381005	uncertain significance	Hypertrophic cardiomyopathy	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1052 of the MYBPC3 protein (p.Met1052Val). This variant is present in population databases (rs730880589, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181002). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002321661	SCV002608539	uncertain significance	Cardiovascular phenotype	2022-12-19	criteria provided, single submitter	clinical testing	The p.M1052V variant (also known as c.3154A>G), located in coding exon 29 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 3154. The methionine at codon 1052 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in a cardiomyopathy cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001209565	SCV004836649	uncertain significance	Hypertrophic cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1052 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 an individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 11/272206 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.