Variant classified as Uncertain Significance - Favor Benign. The p.Thr958Ile var iant in MYBPC3 has been reported in 4 individuals with HCM, one of whom carried another pathogenic MYBPC3 variant (Kabaeva 2005, Ehlermann 2008, Adalsteinsdotti r 2014, Bos 2014). In addition, this variant has been identified by our laborato ry in 3 individuals with HCM, (including one infant whose unaffected parent also carried this variant, as well as one adult who also carried a pathogenic MYBPC3 variant (in cis)) and 1 individual with DCM. This variant has been identified i n 7/61564 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org/; dbSNP rs376504548). Threonine at position 958 is not conserved in evolution and 1 mammal (Bactrian camel) and multiple bird species h ave an isoleucine (Ile) at this position, suggesting that this change may be tol erated. In addition, this change was predicted to be benign using a computationa l tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, while the cli nical significance of the p.Thr958Ile variant is uncertain, collectively these d ata suggest that it is more likely to be benign.

This variant is associated with the following publications: (PMID: 25078086, 21415409, 15823648, 18957093, 29247119, 23861362, 23299917, 25637381, 22958901, 27532257, 24793961, 28416588, 28518168)

The c.2873C>T (p.T958I) alteration is located in exon 27 (coding exon 27) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2873, causing the threonine (T) at amino acid position 958 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

The MYBPC3 c.2873C>T; p.Thr958Ile variant (rs376504548, ClinVar Variation ID: 42664) is reported in the literature in individuals affected with dilated and/or hypertrophic cardiomyopathy (Adalsteinsdottir 2014, Dal Ferro 2017, Kabaeva 2005, McGurk 2023, Ng 2013, Stava 2022, Sepp 2022, Walsh 2017). This variant is found in the general population with an overall allele frequency of 0.016% (43/265,618 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.193). However, given the limited clinical data and lack of functional data, the significance of this variant is uncertain at this time. References: Adalsteinsdottir B et al. Nationwide study on hypertrophic cardiomyopathy in Iceland: evidence of a MYBPC3 founder mutation. Circulation. 2014 Sep 30;130(14):1158-67. PMID: 25078086. Dal Ferro M et al. Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. Heart. 2017 Nov;103(21):1704-1710. PMID: 28416588. Kabaeva Z et al. Returning hypertrophy after surgery in a patient with hypertrophic cardiomyopathy caused by a myosin-binding protein C mutation. Int J Cardiol. 2005 Apr 20;100(2):343-5. PMID: 15823648. 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. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. PMID: 23861362. Stava TT et al. Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. Eur J Prev Cardiol. 2022 Oct 18;29(13):1789-1799. PMID: 35653365. Sepp R et al. The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes. Diagnostics (Basel). 2022 May 3;12(5):1132. PMID: 35626289. 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 isoleucine at codon 958 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15823648, 18957093, 24793961, 25078086, 27532257, 33495597). This variant has been observed in one infant affected with hypertrophic cardiomyopathy, whose unaffected parent also carried this variant, as well as in one adult who also carried a pathogenic MYBPC3 variant in cis (ClinVar SCV000059185.5). This variant has been identified in 43/265618 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including one homozygous individual. 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.

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 958 of the MYBPC3 protein (p.Thr958Ile). This variant is present in population databases (rs376504548, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated and/or hypertrophic cardiomyopathy (PMID: 15823648, 18957093, 24793961, 25078086, 27532257, 28416588, 38456273). ClinVar contains an entry for this variant (Variation ID: 42664). 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.

MYBPC3: BP4

This missense variant replaces threonine with isoleucine at codon 958 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15823648, 18957093, 24793961, 25078086, 27532257, 33495597). This variant has been observed in one infant affected with hypertrophic cardiomyopathy, whose unaffected parent also carried this variant, as well as in one adult who also carried a pathogenic MYBPC3 variant in cis (ClinVar SCV000059185.5). This variant has been identified in 43/265618 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including one homozygous individual. 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.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).