Submissions for variant NM_000256.3(MYBPC3):c.1123G>A (p.Val375Met)

gnomAD frequency: 0.00002  dbSNP: rs727503208

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151143	SCV000198929	uncertain significance	not specified	2014-08-18	criteria provided, single submitter	clinical testing	The Val375Met variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, the clinical significance of the Val375Met variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215230	SCV001386962	uncertain significance	Hypertrophic cardiomyopathy	2024-01-22	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 375 of the MYBPC3 protein (p.Val375Met). This variant is present in population databases (rs727503208, gnomAD 0.004%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 31983221). ClinVar contains an entry for this variant (Variation ID: 164128). 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.
GeneDx	RCV001836739	SCV002097450	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Identified among cohorts of patients with HCM and DCM (Lopes et al., 2015; Walsh et al., 2017; Mazzarotto et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 27532257, 28679633, 31983221)
Ambry Genetics	RCV002433651	SCV002751242	uncertain significance	Cardiovascular phenotype	2022-08-04	criteria provided, single submitter	clinical testing	The p.V375M variant (also known as c.1123G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1123. The valine at codon 375 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopahty (DCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics	RCV002478426	SCV002790023	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486669	SCV004239334	uncertain significance	Cardiomyopathy	2022-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003486669	SCV004358742	uncertain significance	Cardiomyopathy	2023-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 375 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257) and in an individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant has been identified in 5/278004 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.
All of Us Research Program, National Institutes of Health	RCV001215230	SCV004834671	uncertain significance	Hypertrophic cardiomyopathy	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 375 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257) and in an individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221). This variant has been identified in 5/278004 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004558349	SCV005047168	uncertain significance	Hypertrophic cardiomyopathy 4	2024-01-27	criteria provided, single submitter	clinical testing	The MYBPC3 c.1123G>A (p.Val375Met) variant has been reported in several individuals with cardiomyopathy (Lopes LR et al., PMID: 25351510; Walsh R et al., PMID: 27532257; Mazzarotto F et al., PMID: 31983221). This variant has been reported in the ClinVar database as a variant of uncertain significance by multiple submitters (ClinVar Variation ID: 164128). This variant is observed on 39/1,612,772 alleles in the general population (gnomAD v4.0.0). Computational predictors are uncertain as to the impact of this variant on MYBPC3 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the MYBPC3 c.1123G>A (p.Val375Met) variant is uncertain at this time.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001836739	SCV005877381	uncertain significance	not provided	2024-10-15	criteria provided, single submitter	clinical testing	The MYBPC3 c.1123G>A; p.Val375Met variant (rs727503208; ClinVar ID: 164128) is reported in the literature in several individuals affected with hypertrophic cardiomyopathy or dilated cardiomyopathy (Lopes 2015, Mazzarotto 2020, Walsh 2017). This variant is found in the general population with an overall allele frequency of 0.002% (5/278,004 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.641). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. PMID: 25351510. Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020 Feb 4;141(5):387-398. PMID: 31983221. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257.