Reported in individuals with HCM and DCM, and in one individual with sudden unexplained death in infancy (Niimura et al., 2002; Ho et al., 2009; Coppini et al., 2014; Burns et al, 2017; Walsh et al., 2017; Cirino et al., 2017; Dewar et al., 2017); 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: 21415409, 15115610, 24503780, 11815426, 20031602, 28790153, 28679633, 29030401, 25524337, 28807990, 27532257, 28986452, 33782553, KrylovaNS2020, 33673806, 35653365)

The p.Arg1002Gln variant in MYBPC3 has been reported in 3 individuals with HCM (Niimura 2002, Ho 2009 and LVOD unpublished data). This variant was also identified by our laboratory in 1 individual with DCM and in 1 individual with giant right atrium and arrhythmia (LMM unpublished data). In addition, this variant was identified in 4/62092 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Arginine (Arg) at position 1002 is not conserved in evolutionarily distant species and the change to glutamine (Gln) is present in several birds. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Arg1002Gln variant is uncertain, the presence of the variant amino acid in multiple bird species suggests that it is more likely to be benign.,The Arg1002Gln variant in MYBPC3 has been reported in 3 individuals with HCM (Niimura 2002, Ho 2009 and LVOD unpublished data). This variant was also identified by our laboratory in 1 individual with DCM and in 1 individual with giant right atrium and arrhythmia (LMM unpublished data). In addition, this variant was identified in 4/62092 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Arginine (Arg) at position 1002 is not conserved in evolutionarily distant species and the change to glutamine (Gln) is present in several birds. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Arg1002Gln variant is uncertain, the presence of the variant amino acid in multiple bird species suggests that it is more likely to be benign.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 (19 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 286 heterozygotes, 2 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin i-set domain (DECIPHER). (I) 0709 - Another missense variant comparable to the one identified in this case has strong previous evidence for being benign. A comparable variant, p.(Arg1002Trp), has been reported 12 times as likely benign/benign in ClinVar. (SB) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as VUS in heterozygous patients with HCM. There have also been limited reports of this variant classified as VUS in patients with DCM and sudden unexplained death (ClinVar, http://cardiodb.org, PMIDs: 11815426, 28790153, 28807990, 29030401). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1002 of the MYBPC3 protein (p.Arg1002Gln). This variant is present in population databases (rs727504235, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 11815426, 27532257, 28790153, 28807990, 29030401, 33673806, 33782553, 37652022). ClinVar contains an entry for this variant (Variation ID: 177622). 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 arginine with glutamine at codon 1002 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 performed for this variant. This variant has been reported in at least four individuals affected with hypertrophic cardiomyopathy (PMID: 11815426, 28790153, 27532257, 32841044, 33495597, 33673806, 33782553; Burns 2019, dissertation, University of Sydney) and in one infant affected with sudden death (PMID: 28807990). This variant has also been identified in 16/267108 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.R1002Q variant (also known as c.3005G>A), located in coding exon 29 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3005. The arginine at codon 1002 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and sudden unexplained death (SUD) cohorts; however, clinical details are limited (Niimura H et al. Circulation, 2002 Jan;105:446-51; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10; Dewar LJ et al. Circ Cardiovasc Genet, 2017 Aug;10; Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Oakley CE et al. Cell Res., 2004 Apr;14:95-110). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

This missense variant replaces arginine with glutamine at codon 1002 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 performed for this variant. This variant has been reported in at least four individuals affected with hypertrophic cardiomyopathy (PMID: 11815426, 28790153, 27532257, 32841044, 33495597, 33673806, 33782553; Burns 2019, dissertation, University of Sydney) and in one infant affected with sudden death (PMID: 28807990). This variant has also been identified in 16/267108 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.