Submissions for variant NM_000432.4(MYL2):c.401A>C (p.Glu134Ala)

gnomAD frequency: 0.00029  dbSNP: rs143139258

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036404	SCV000060059	uncertain significance	Hypertrophic cardiomyopathy	2019-04-05	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gnomad: 0.033 in NFE population, HGMD: Whiffin (2017) Genet Med 19: 1151 PubMed: 28518168 Additional literature report − classed as VUS. See Supplementary Table S1. (only additional report, refers Burghardt et al). %7C ClinVar: VUS by Invitae, Ambry, EGL , LP by University of Washington, Eric and Hanna Klessmann Institute. Reported in multiple individuals with cardiomyopathy but frequency higher than expected for a pathogenic variant. Conflicting information - VUS.
CSER _CC_NCGL, University of Washington	RCV000036404	SCV000190446	likely pathogenic	Hypertrophic cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of hypertrophic cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Invitae	RCV000154179	SCV000254534	uncertain significance	Hypertrophic cardiomyopathy 10	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 134 of the MYL2 protein (p.Glu134Ala). This variant is present in population databases (rs143139258, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20173211, 24111713, 25524337, 27483260, 27600940). ClinVar contains an entry for this variant (Variation ID: 43475). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects MYL2 function (PMID: 23343568). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV000248445	SCV000319557	uncertain significance	Cardiovascular phenotype	2022-12-30	criteria provided, single submitter	clinical testing	The p.E134A variant (also known as c.401A>C), located in coding exon 6 of the MYL2 gene, results from an A to C substitution at nucleotide position 401. The glutamic acid at codon 134 is replaced by alanine, an amino acid with dissimilar properties. This variant has been reported in hypertrophic cardiomyopathy, dilated cardiomyopathy, and sudden cardiac arrest cohorts; however, in several cases clinical detail was limited, this variant was reported to co-occur with other cardiac-related genes, and/or this variant was also detected in unaffected family members (Olivotto I et al. Mayo Clin Proc. 2008;83:630-8; Di Donna P et al. Europace. 2010;12:347-55; Berge KE et al. Clin Genet. 2014;86:355-60; Cecconi M et al. Int J Mol Med. 2016;38(4):1111-24; Stpie-Wojno M et al. Pol Arch Intern Med. 2018;12; Mademont-Soler I et al. PLoS ONE. 2017;12(8):e0181465; Klauke B et al. PLoS One, 2017 Dec;12:e0189489;; Gavotto A et al. BMC Pediatr, 2019 11;19:462). This variant has also been detected in population-based cohorts and exome cohorts with unclear cardiovascular history (Bick AG. Am J Hum Genet. 2012;91(3):513-9; Andreasen C et al. Eur J Hum Genet. 2013;21:918-28; Dorschner MO et al. Am J Hum Genet. 2013 Oct;93:631-40). An in vitro study suggested that this alteration may reduce actin binding (Burghardt TP et al. Biochemistry. 2013;52:1249-59). 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.
Eurofins Ntd Llc (ga)	RCV000119379	SCV000342245	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000119379	SCV000696696	uncertain significance	not provided	2016-01-20	criteria provided, single submitter	clinical testing	Variant summary: c.401A>C affects a conserved nucleotide, resulting in amino acid change from Glu to Ala. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 19/121996 control chromosomes at a frequency of 0.0001557, predominantly observed in Latino and non-Finnish European subpopulations with MAF of 0.0003455 and 0.0002248 respectively in ExAC. The frequencies exceed the maximal expected frequency of a pathogenic allele (0.000075). This variant has been reported in multiple HCM pts and functional study showed that the actin binding in contraction is compromised by the E134A mutation (Burghardt_2013). An internal LCA sample carried this variant with co-occurrence of a pathogenic MYBPC3 variant (c.1504C>T, p.R502W). Via Clinivar, two clinical labs list variant with classification of likely pathogenic, one classified it as pathogenic, and another lab classified variant as VUS. Taking all evidence into consideration, although this variant has been reported in multiple affected individuals, it is also present at a relatively high frequency in the general population, and thus the pathogenicity of this variant is unclear at this moment; hence, this variant is classified as a variant of unknown significance until more information becomes available.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624611	SCV000740466	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2017-02-21	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000154179	SCV000883094	likely pathogenic	Hypertrophic cardiomyopathy 10	2018-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776290	SCV000911581	uncertain significance	Cardiomyopathy	2023-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 134 of the MYL2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may impact RNA splicing. A functional study using a cardiac papillary muscle fiber system has shown that this variant reduces actin binding in contraction (PMID: 23343568). However, clinical relevance of this observation is not clear. This variant has been reported in at least six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 23396983, 24111713, 31323898, 33495596, 33495597, 33732734). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 34935411, 35026164), and in one individual affected with respiratory syncytial virus-associated sudden death and an unaffected carrier parent (PMID: 31771554). This variant has been identified in 57/282826 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776290	SCV001333013	uncertain significance	Cardiomyopathy	2020-02-24	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000119379	SCV001449766	pathogenic	not provided	2015-01-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000154179	SCV002581410	uncertain significance	Hypertrophic cardiomyopathy 10	2022-02-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000036404	SCV004845828	uncertain significance	Hypertrophic cardiomyopathy	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 134 of the MYL2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may impact RNA splicing. A functional study using a cardiac papillary muscle fiber system has shown that this variant reduces actin binding in contraction (PMID: 23343568). However, clinical relevance of this observation is not clear. This variant has been reported in at least six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 23396983, 24111713, 31323898, 33495596, 33495597, 33732734). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 34935411, 35026164), and in one individual affected with respiratory syncytial virus-associated sudden death and an unaffected carrier parent (PMID: 31771554). This variant has been identified in 57/282826 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.
Leiden Muscular Dystrophy (MYL2)	RCV000119379	SCV000154286	not provided	not provided		no assertion provided	not provided
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491626	SCV000298100	likely pathogenic	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678725	SCV000804897	likely pathogenic	Primary dilated cardiomyopathy	2016-09-22	no assertion criteria provided	clinical testing