BS1, BS4_supporting, PP3

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This missense variant replaces arginine with histidine at codon 238 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 21750094, 24503780, 25635128, 27532257, 30847666, 32880476) and in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 25/247534 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary 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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 238 of the MYBPC3 protein (p.Arg238His). This variant is present in population databases (rs727504396, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated or hypertrophic cardiomyopathy (PMID: 21750094, 24503780, 25635128, 27532257, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 177910). 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.

Variant classified as Uncertain Significance - Favor Benign. The p.Arg238His var iant in MYBPC3 has been reported in 1 individual with DCM (Waldmuller 2011). Thi s variant has been identified by our laboratory in 1 Asian adult with HCM who ca rried another pathogenic MYBPC3 variant and 1 Caucasian family with several memb ers having various cardiomyopathy presentations including LVNC, mild LVH and sev ere, neonatal DCM. In this family, two infants with neonatal DCM had the Arg238H is variant in addition to a variant in ACTC1. The ACTC1 variant was present in three paternal relatives who had either mild LVH or LVNC and is suspected to be disease causing. The MYBPC3 Arg238His variant was inherited from the unaffected mother. Computational prediction tools and conservation analysis suggest that t he p.Arg238His variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. However, this variant has been ident ified in 0.05% (17/33486) of Latino chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504396). This variant h as been reported in ClinVar (Variant ID:177910). In summary, the clinical signif icance of the p.Arg238His variant is uncertain and its frequency suggests that i t is less likely to be disease causing on its own. ACMG/AMP Criteria applied: PP 3; BS1.

Variant summary: MYBPC3 c.713G>A (p.Arg238His) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 247534 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (0.0001 vs 0.001), allowing no conclusion about variant significance. c.713G>A has been reported in the literature in individuals affected with Hypertrophic and Dilated Cardiomyopathy (example, Waldmuller_2011, Walsh_2017, Chae_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic or Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces arginine with histidine at codon 238 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious 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 dilated cardiomyopathy (PMID: 21750094, 24503780, 25635128, 27532257, 30847666, 32880476, 35026164) and in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 25/247534 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Identified in individuals with cardiomyopathy (PMID: 21750094, 24503780, 27532257, 37652022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 27532257, 29687901, 32880476, 25635128, 30847666, 21750094, 37652022, 35026164, 40225148)