This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1139 of the MYBPC3 protein (p.Val1139Ile). This variant is present in population databases (rs373519667, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42713). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

The c.3415G>A (p.V1139I) alteration is located in exon 31 (coding exon 31) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 3415, causing the valine (V) at amino acid position 1139 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

BS1, BP4, PS4_moderate

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35629155, 37652022, 27532257, 35838873)

This missense variant replaces valine with isoleucine at codon 1139 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 an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 22/268026 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 Val1139Ile variant (MYBPC3) has been identified in 1/3308 of African America n chromosomes by the NHLBI Exome Sequencing Project in a broad population (http: //evs.gs.washington.edu/EVS). Valine (Val) at position 1139 is highly conserved in mammals and across evolutionarily distant species, though computational analy ses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. Additional inform ation is needed to fully assess the clinical significance of the Val1138Ile vari ant.

This missense variant replaces valine with isoleucine at codon 1139 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 an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has also been identified in 22/268026 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.

Variant summary: MYBPC3 c.3415G>A (p.Val1139Ile) results in a conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 1607962 control chromosomes, predominantly at a frequency of 0.00052 within the African or African-American subpopulation in the gnomAD database (v 4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (5.3e-05 vs 0.001), allowing no conclusion about variant significance. c.3415G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Bick_2012, Walsh_2012) without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22958901, 27532257). ClinVar contains an entry for this variant (Variation ID: 42713). Based on the evidence outlined above, the variant was classified as uncertain significance.

The MYBPC3 c.3415G>A variant is predicted to result in the amino acid substitution p.Val1139Ile. This variant was reported as uncertain significance in individuals with hypertrophic cardiomyopathy and/or muscular dystrophy (Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Kurzlechner et al. 2022. PubMed ID: 35629155). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.