The Thr737Met variant in MYBPC3 has not been reported in the literature though i t has been identified in 1 individual with HCM out of >1900 Caucasian probands ( 3800 chromosomes) tested by our laboratory. This low frequency is consistent wit h a pathogenic role. However, threonine (Thr) at position 737 is not completely conserved in evolution, suggesting that a change may be tolerated. Furthermore, this variant was predicted to be benign using a novel computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well -established clinical significance. This tool's benign interpretation is estimat ed to be correct 89% of the time, which suggests but does not prove that this va riant is benign (Jordan 2011). In summary, the clinical significance of this var iant cannot be determined without additional studies.

Identified in patients with cardiomyopathy in published literature (PMID: 22958901, 31983221, 27532257, 33782553, 23861362, Rippert et al., 2023, 37652022, 32841044, 33495597); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 23861362, 21310275, 31983221, 32746448, 33782553, 27532257, 32841044, Rippert2023[article], 37652022, 33495597)

The c.2210C>T (p.T737M) alteration is located in exon 23 (coding exon 23) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2210, causing the threonine (T) at amino acid position 737 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.008% (21/280356) total alleles studied. The highest observed frequency was 0.015% (19/128236) of European (non-Finnish) alleles. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

BP4

The MYBPC3 c.2210C>T; p.Thr737Met variant (rs199893357, ClinVar Variation ID: 42608) is reported in the literature in individuals affected with dilated and/or hypertrophic cardiomyopathy (Bick 2012, Burstein 2021, Harper 2021, Helms 2020, Mazzarotto 2020, McGurk 2023, Rippert 2023, Walsh 2017). This variant is found in the general population with an overall allele frequency of 0.008% (21/280,356 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.297). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bick AG et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am J Hum Genet. 2012 Sep 7;91(3):513-9. PMID: 22958901. Burstein DS et al. Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. Pediatr Res. 2021 May;89(6):1470-1476. PMID: 32746448. Harper AR et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat Genet. 2021 Feb;53(2):135-142. PMID: 33495597. Helms AS et al Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. Circ Genom Precis Med. 2020 Oct;13(5):396-405. PMID: 32841044. Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020 Feb 4;141(5):387-398. PMID: 31983221. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Rippert AL et al. Evaluating the Utility of a New Pathogenicity Predictor for Pediatric Cardiomyopathy. Human Mutation, 2023 Oct; https://doi.org/10.1155/2023/8892833. 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.

This missense variant replaces threonine with methionine at codon 737 of the MYBPC3 protein. Computational prediction suggests that this variant may have a neutral impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 31983221 and 32746448). This variant has also been identified in 21/280356 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.

The MYBPC3 c.2210C>T (p.Thr737Met) variant has been reported in at least 9 individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy and also has been reported in the literature in at least 4 unaffected individuals (Alfares AA et al., PMID: 25611685; Bick AG et al., PMID: 22958901; Burstein DS et al., PMID: 32746448; Helms AS et al., PMID: 32841044; Harper AR et al., PMID: 33495597; Ho CY et al., PMID: 30297972; Kurzlechner LM et al., PMID: 35629155.; Mazzarotto F et al., PMID: 31983221; Miller RJH et al., PMID: 31199839; Ng D et al., PMID: 23861362; Walsh R et al., PMID: 27532257). The highest population minor allele frequency in the population database genome aggregation database (v.4.1.0) is 0.02% in the European (non-Finnish) population which is higher than expected for disorder (https://cspec.genome.network/cspec/ui/svi/doc/GN095). This variant has been reported in the ClinVar database as a germline likely benign variant by 1 submitter and a variant of uncertain significance by 9 submitters (Variation ID: 42608). Computational predictors, including a predictor of subdomain protein stability in MYBPC3, suggest that the variant does not impact MYBPC3 function (Thompson AD et al., PMID: 33782553). Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 737 of the MYBPC3 protein (p.Thr737Met). This variant is present in population databases (rs199893357, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of MYBPC3-related conditions (PMID: 27532257, 31983221, 32746448, 33782553; internal data). ClinVar contains an entry for this variant (Variation ID: 42608). 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 tolerated. 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.

This missense variant replaces threonine with methionine at codon 737 of the MYBPC3 protein. Computational prediction suggests that this variant may have a neutral impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 31983221 and 32746448). This variant has also been identified in 21/280356 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.