ClinVar Genomic variation as it relates to human health

We previously classified the MYL3 Arg154His variant as likely pathogenic (2015). However, recent review found the MYL3 Arg154His variant is reported 8 times in GnomAD (allele frequency 0.000028, highest sub-population frequency of 0.00005). According to the adapted ACMG/AMP criteria the sub-population frequency is too high to allow PM2 to be applied (Kelly et al., 2018). In total the variant has been reported in over 15 other HCM probands by laboratories and in the literature (Walsh et al., 2017, Miller et al., 2013; Poetter et al., 1996; LMM, Pers. Comm.; GeneDx, Pers. Comm.), as well as in ARVC (Murray et al., 2018) and unaffected phenotypes (Bick et al., 2012). The ARVC and unaffected patients, suggest that this variant may not be causal or perhaps require additional risk/modifying factors to cause disease expression. More importantly, because the variant is seen at an elevated frequency this suggests that the occurrence of the variant in HCM probands is incidental, and because PM2 criteria has not been met, the probands have not been considered as evidence. In silico tools are in agreement of a deleterious role. Based on this information we have classified MYL3 Arg154His 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 154 of the MYL3 protein (p.Arg154His). This variant is present in population databases (rs104893749, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and/or restrictive cardiomyopathy (PMID: 8673105, 27532257, 28790153, 29253866, 29709087, 35626289). ClinVar contains an entry for this variant (Variation ID: 14062). 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 tolerated. Experimental studies have shown that this missense change affects MYL3 function (PMID: 22131351). This variant disrupts the p.Arg154 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been observed in individuals with MYL3-related conditions (PMID: 23283745, 31110529), 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.

This missense variant replaces arginine with histidine at codon 154 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a lower affinity for the myosin heavy chain (PMID: 22131351). This variant has been reported in a young boy affected with massive mid left ventricular chamber obstruction (PMID: 8673105), in a few individuals affected with hypertrophic cardiomyopathy cases (PMID: 23054336, 27532257, 28408708, 28790153) and in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29709087). One of the individuals affected with hypertrophic cardiomyopathy also carried a pathogenic truncation in MYBPC3 that could explain the observed disease (PMID: 23054336). This variant has also been identified in 8/282774 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.

The p.Arg154His variant in MYL3 has been identified in at least 7 individuals with HCM (Poetter 1996, Ross 2017, Walsh 2016, Wojciak pers. comm., Ambry pers. comm, LMM data). The variant segregated with disease in one affected family member (Ross 2017). This variant has also been identified in 8/277124 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104893749). In vitro functional studies provide some evidence that the p.Arg154His variant may impact protein function (Lossie 2012); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg154His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg154His variant is uncertain. ACMG/AMP criteria applied: PP3, PS3_Supporting.

Reported multiple times in association with hypertrophic cardiomyopathy and in one patient with arrhythmogenic right ventricular cardiomyopathy (Poetter et al., 1996; Miller et al., 2013; Burns et al., 2017; Ingles et al., 2017; Ross et al., 2017; Walsh et al., 2017; Murray et al., 2018), including one patient reported to be homozygous for the p.(R154H) variant with childhood-onset cardiomyopathy and subsequent heart transplant (Klauke et al., 2017); Observed in two individuals without hypertrophic cardiomyopathy from the offspring cohort in the Framingham Heart Study (Bick et al., 2012); Published functional study suggests that p.(R154H) causes reduced binding affinity for the cardiac myosin heavy chain (Lossie et al., 2012); however, it is unclear what impact this variant may have on protein function in vivo; 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: 23054336, 27532257, 28152038, 28615295, 17142342, 28790153, 29709087, 30706179, 22131351, 29253866, 8673105, 28408708, 22958901)

This missense variant replaces arginine with histidine at codon 154 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a lower affinity for the myosin heavy chain (PMID: 22131351). This variant has been reported in a young boy affected with massive mid left ventricular chamber obstruction (PMID: 8673105), in a few individuals affected with hypertrophic cardiomyopathy cases (PMID: 23054336, 27532257, 28408708, 28790153) and in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29709087). One of the individuals affected with hypertrophic cardiomyopathy also carried a pathogenic truncation in MYBPC3 that could explain the observed disease (PMID: 23054336). This variant has also been identified in 8/282774 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.

The p.R154H variant (also known as c.461G>A), located in coding exon 4 of the MYL3 gene, results from a G to A substitution at nucleotide position 461. The arginine at codon 154 is replaced by histidine, an amino acid with highly similar properties.This variant has been identified in the heterozygous state in multiple individuals diagnosed with hypertrophic cardiomyopathy (HCM) (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Walsh R et al. Genet. Med., 2017 02;19:192-203; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10; Murray B et al. J. Cardiovasc. Electrophysiol., 2018 07;29:1004-1009; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67). It has also been seen in the homozygous state in one individual with sporadic restricted cardiomyopathy whose heterozygous parents had no clinical cardiac features (Klauke B et al. PLoS ONE, 2017 Dec;12:e0189489). This variant has also 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). An experimental study has shown that this variant may contribute to reduced binding affinity of the myosin heavy chain, but the clinical relevance of that change is unclear (Lossie J et al. Cardiovasc. Res., 2012 Mar;93:390-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.