ClinVar Genomic variation as it relates to human health

This missense variant replaces proline with leucine at codon 371 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 three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32830170, 33487615). This variant has been identified in 6/245804 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 missense variant replaces proline with leucine at codon 371 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 three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32830170, 33487615). This variant has been identified in 6/245804 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 p.P371L variant (also known as c.1112C>T), located in coding exon 13 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1112. The proline at codon 371 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Nakashima Y et al. Circ J, 2020 Sep;84:1846-1853). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Identified in patients with cardiomyopathy in the published literature (Walsh et al., 2017; Ito et al., 2017; Li et al., 2018); At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27532257, 28679633, 30371277, 31397097)

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 371 of the MYBPC3 protein (p.Pro371Leu). This variant is present in population databases (rs397515887, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or left ventricular noncompaction (PMID: 27532257, 31397097, 32830170). ClinVar contains an entry for this variant (Variation ID: 181060). 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. This variant disrupts the p.Pro371 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 35208637), which suggests that this may be a clinically significant amino acid residue. 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.