The S1191L variant of uncertain significance in the MYBPC3 gene has been reported in association with HCM (Bos et al., 2014; Lopes et al., 2015; Walsh et al., 2017); however these reports do not provide specific clinical or segregation data and they do not clarify if other variants were identified in these individuals. S1191L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, the S1191L variant is observed in 3/17,244 (0.01%) East Asian alleles in large population cohorts (Lek et al., 2016). Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

The p.S1191L variant (also known as c.3572C>T), located in coding exon 32 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3572. The serine at codon 1191 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and cardiomyopathy cohorts (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 02;19:192-203; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799). 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.

This missense variant replaces serine with leucine at codon 1191 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 at least 2 individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant has been identified in 4/248956 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.

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1191 of the MYBPC3 protein (p.Ser1191Leu). This variant is present in population databases (rs761545914, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 524959). 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.

This missense variant replaces serine with leucine at codon 1191 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.4, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 2 individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant has been identified in 4/248956 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.

ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYBPC3 Version 1.0.0: BP4

The MYBPC3 c.3572C>T variant is predicted to result in the amino acid substitution p.Ser1191Leu. This variant was reported as a variant of uncertain significance in individuals with hypertrophic cardiomyopathy (Table S1, Bos et al. 2014. PubMed ID: 24793961; Table S1, Lopes et al. 2014. PubMed ID: 25351510; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Table S10, Stava et al. 2022. PubMed ID: 35653365). However, this variant was also found in an affected individual who also carried a causative variant in MYBPC3 (patient #56 in Table S2, Field et al. 2022. PubMed ID: 34400558). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.