The p.Arg1079Gln variant in MYH7 has been identified in 3 individuals with cardiomyopathy (1 with DCM and 2 with HCM) and segregated with disease in one affected family member (Waldmüller 2011, Cecconi 2016, LMM data). In addition, this variant was identified by our laboratory in 1 individual with HCM and 1 affected family member, who both also carried a pathogenic variant in MYBPC3. This variant has been identified in 2/129124 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID:177826). Computational prediction tools and conservation analysis suggest that the p.Arg1079Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg1079Gln variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Supporting, BP4.

This missense variant replaces arginine with glutamine at codon 1079 of the MYH7 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 several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27600940, 27532257, 33495597), dilated cardiomyopathy (PMID: 21750094), or systemic amyloidosis with a cardiac involvement (PMID: 24749114). This variant has also been reported in two families with hypertrophic cardiomyopathy, including three affected carriers and three unaffected carriers (PMID: 20359594, 28687478, 28790153). This variant has been identified in 2/282774 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 arginine with glutamine at codon 1079 of the MYH7 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 several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27600940, 27532257, 33495597, 38489124), dilated cardiomyopathy (PMID: 21750094), or systemic amyloidosis with cardiac involvement (PMID: 24749114). This variant has also been reported in two families with hypertrophic cardiomyopathy, including three affected carriers and three unaffected carriers (PMID: 20359594, 28687478, 28790153). This variant has been identified in 2/282774 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 variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2.

This MYH7 Arg1079Gln variant is a rare occurrence in the general population; it is not observed in the 1000 genomes project (http://www.1000genomes.org/), and is a singleton event in the Exome Aggregation Consortium dataset (MAF= 0.000008, http://exac.broadinstitute.org/). We have identified the MYH7 Arg1079Gln variant in an HCM proband where two additional MYBPC3 variants have also been observed in the family (Girolami F, et al., 2010). One of the additional variants (MYBPC3 Gln969Ter) is well described as disease-causing. Segregation analysis showed this MYH7 Arg1079Gln variant to be present in one other affected family member (who also carries the disease causative MYBPC3 Gln969Ter variant). The MYH7 Arg1079Gln has been identified in a general population (Bick AG, et al., 2012) and 2 HCM probands (Alfares AA et al., 2015; Cecconi M et al., 2016), no further evidence is provided in these studies to support a pathogenic role. This variant has also been identified in one DCM patient (Waldmüller S, et al., 2011) and double heterozygous amyloidosis with HCM case (Ebrille E, et al., 2013). Predictions from in silico tools are contradictory with SIFT and MutationTaster predicting the amino acid substitution to be "deleterious" and "disease-causing". PolyPhen-2 predicts the impact of this variant to be "benign" (note: no prediction is made by PolyPhen-HCM). Due to limited segregation analysis due to small number of informative individuals, and co-occurrence with a MYBPC3 variant that explains the disease phenotype, we classify this MYH7 Arg1079Gln variant as one of "uncertain significance".

The p.R1079Q variant (also known as c.3236G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide position 3236. The arginine at codon 1079 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cohorts, and has been reported in combination with alterations in other cardiac-related genes (Waldm&uuml;ller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Ebrille E et al. Glob Cardiol Sci Pract, 2013 Dec;2013:405-8; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; P&eacute;rez-S&aacute;nchez I et al. Rev Esp Cardiol (Engl Ed), 2018 Mar;71:146-154). This alteration has also been reported in families with HCM, and reported in both affected and unaffected family members (Girolami F et al. J Am Coll Cardiol, 2010 Apr;55:1444-53; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:). This variant has been reported in the Framingham Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This amino acid position is not 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 sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1079 of the MYH7 protein (p.Arg1079Gln). This variant is present in population databases (rs727504342, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20359594, 21750094, 24749114, 25611685, 27532257, 27600940, 28687478, 28790153; internal data). ClinVar contains an entry for this variant (Variation ID: 177826). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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.