ClinVar Miner

Submissions for variant NM_000432.3(MYL2):c.401A>C (p.Glu134Ala) (rs143139258)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248445 SCV000319557 uncertain significance Cardiovascular phenotype 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678725 SCV000804897 likely pathogenic Dilated cardiomyopathy 2016-09-22 no assertion criteria provided clinical testing
Color RCV000776290 SCV000911581 uncertain significance Cardiomyopathy 2018-05-21 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the EF hand domain3 of the MYL2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study using a cardiac papillary muscle fiber system has suggested that this variant reduces actin binding in contraction (PMID: 23343568). However, clinical significance of this finding is not clear. This variant has been reported in several European individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 23396983, 24111713). Although these data are suggestive of a pathogenic role of this variant, this variant has also been identified in 54/277164 chromosomes (42/126684 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119379 SCV000342245 uncertain significance not provided 2016-06-01 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
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
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000154179 SCV000254534 uncertain significance Familial hypertrophic cardiomyopathy 10 2018-12-03 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 reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 24111713, 25524337, 27600940, 27483260). ClinVar contains an entry for this variant (Variation ID: 43475), where this variant was identified in several other individuals affected with HCM. Segregation studies have not been reported for this variant. An experimental study evaluated the role of mutant protein using a cardiac papillary muscle fiber system, and reported that this variant affected MYL2 protein function by reducing actin binding (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.
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
Leiden Muscular Dystrophy (MYL2) RCV000119379 SCV000154286 not provided not provided no assertion provided not provided
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.