Submissions for variant NM_000258.3(MYL3):c.461G>A (p.Arg154His)

gnomAD frequency: 0.00002  dbSNP: rs104893749

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000766487	SCV000059677	uncertain significance	not provided	2019-04-04	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000766487	SCV000250969	uncertain significance	not provided	2022-04-11	criteria provided, single submitter	clinical testing	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)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000015106	SCV000256645	uncertain significance	Hypertrophic cardiomyopathy 8	2019-06-12	criteria provided, single submitter	research	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.
Ambry Genetics	RCV000253839	SCV000318462	uncertain significance	Cardiovascular phenotype	2024-07-25	criteria provided, single submitter	clinical testing	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). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552674	SCV000623772	uncertain significance	Hypertrophic cardiomyopathy	2024-11-19	criteria provided, single submitter	clinical testing	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170903	SCV001333535	uncertain significance	Cardiomyopathy	2018-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170903	SCV001352583	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000766487	SCV002502349	uncertain significance	not provided	2022-03-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000015106	SCV002794168	uncertain significance	Hypertrophic cardiomyopathy 8	2021-12-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000552674	SCV004843321	uncertain significance	Hypertrophic cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000015106	SCV005878781	uncertain significance	Hypertrophic cardiomyopathy 8	2024-01-09	criteria provided, single submitter	clinical testing	The MYL3 c.461G>A; p.Arg154His variant (rs104893749) is reported in the literature in several individuals affected with cardiomyopathy (Alfares 2015, Burns 2017, Ingles 2017, Klauke 2017, McGurk 2023, Miller 2013, Murray 2018, Poetter 1996, Ross 2017, Sepp 2022, Walsh 2017). The variant is also reported in a homozygous state in a patient with restrictive cardiomyopathy (Klauke 2017), while both parents of the patient were reported as healthy heterozygous carriers. This variant is reported in ClinVar (Variation ID: 14062). This variant is found in the general population with an overall allele frequency of 0.003% (8/282774 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another variant at this codon (c.460C>T; p.Arg154Cys) has been reported in individuals with hypertrophic cardiomyopathy, but is currently considered a variant of uncertain significance (Alfares 2015, McGurk 2023, Walsh 2017, Zou 2013). In vitro functional studies of p.Arg154His revealed similar defects in the binding of variant MYL3 protein to myosin heavy chain when compared to other pathogenic variants in the gene (Lossie 2012). However, these functional observations are difficult to interpret, as the exact molecular mechanisms underlying the physiological defects associated with MYL3 disruption remain unknown. Computational analyses predict that this variant is deleterious (REVEL: 0.911). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Alfares AA et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8. PMID: 25611685. Burns C et al. Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. Circ Cardiovasc Genet. 2017 Aug;10(4):e001666. PMID: 28790153. Ingles J et al. Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. Circ Cardiovasc Genet. 2017 Apr;10(2):e001620. PMID: 28408708. Klauke B et al. High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation. PLoS One. 2017 Dec 18;12(12):e0189489. PMID: 29253866. Lossie J et al. Mutations of ventricular essential myosin light chain disturb myosin binding and sarcomeric sorting. Cardiovasc Res. 2012 Mar 1;93(3):390-6. PMID: 22131351. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Miller EM et al. Uptake of cardiac screening and genetic testing among hypertrophic and dilated cardiomyopathy families. J Genet Couns. 2013 Apr;22(2):258-67. doi: 10.1007/s10897-012-9544-4. PMID: 23054336. Murray B et al. Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). J Cardiovasc Electrophysiol. 2018 Jul;29(7):1004-1009. PMID: 29709087. Poetter K et al. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet. 1996 May;13(1):63-9. PMID: 8673105. Ross SB et al. Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. Circ Cardiovasc Genet. 2017 Jun;10(3):e001671. PMID: 28615295. Sepp R et al. The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes. Diagnostics (Basel). 2022 May 3;12(5):1132. PMID: 35626289. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. Zou Y et al. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep. 2013 Jun;40(6):3969-76. PMID: 23283745.
OMIM	RCV000015106	SCV000035363	pathogenic	Hypertrophic cardiomyopathy 8	1996-05-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (MYL3)	RCV000015106	SCV000045770	not provided	Hypertrophic cardiomyopathy 8	2012-03-18	no assertion provided	curation
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491772	SCV000298146	uncertain significance	Cardiomyopathy, familial restrictive, 1	2016-05-01	no assertion criteria provided	clinical testing