ClinVar Miner

Submissions for variant NM_000432.4(MYL2):c.401A>C (p.Glu134Ala) (rs143139258)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211874 SCV000060059 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
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 Familial hypertrophic cardiomyopathy 10 2020-09-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 134 of the MYL2 protein (p.Glu134Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs143139258, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 24111713, 25524337, 27600940, 27483260). ClinVar contains an entry for this variant (Variation ID: 43475). This variant has been reported to affect MYL2 protein function (PMID: 23343568). 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 2020-03-25 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 cohorts and a sudden cardiac arrest cohort; however, in several cases clinical detail was limited, and this variant has been reported to co-occur with other variants in MYL2 and other cardiac-related genes (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;​ Stępień-Wojno M et al. Pol Arch Intern Med. 2018;12;​ Mademont-Soler I et al. PLoS ONE. 2017;12(8):e0181465). This variant has also been detected in exome cohorts with unclear cardiovascular history and population-based cohorts (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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Familial hypertrophic cardiomyopathy 10 2018-11-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776290 SCV000911581 uncertain significance Cardiomyopathy 2021-01-20 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with alanine at codon 134 of the MYL2 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).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 five unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 23396983, 24111713, 31323898). This variant has also been identified in 57/282826 chromosomes (45/129164 non-Finnish European 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119379 SCV001148828 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000776290 SCV001333013 uncertain significance Cardiomyopathy 2018-05-15 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000119379 SCV001449766 pathogenic not provided 2015-01-05 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (MYL2) RCV000119379 SCV000154286 not provided not provided no assertion provided not provided
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia 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

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