MYL2 A13T - GET-Evidence

Curation:
Currentness:

MYL2 A13T

(MYL2 Ala13Thr)


Short summary

This rare variant is implicated in causing late-onset familial hypertrophic cardiomyopathy. The variant has been found in five affected Caucasian individuals (in four families), but affected non-carriers and unaffected carriers have also been observed. No statistically significant enrichment of this variant in cases vs. controls has been shown.

Variant evidence
Computational 3

Variant is conserved in pig and chicken cardiac a (but not in rat, mouse or chicken cardiac b), but it is in an active domain and in a gene associated with this disease.

See Szczesna D et al. 2001 (11102452), Szczesna-Cordary D et al. 2004 (14594949).

Functional 4

The secondary structure and Ca sensitivity is affected in vitro, and rabbit psoas and porcine cardiac myofibrils show decreased sensitivity to Ca.

See Szczesna D et al. 2001 (11102452), Roopnarine O 2003 (12668451), Szczesna-Cordary D et al. 2004 (14594949).

Case/Control

Not statistically significant (p = 0.22).

See Poetter K et al. 1996 (8673105), Andersen PS et al. 2001 (11748309).

Familial -1

Without Harvard LMM pedigree and excluding Anderson et al’s phenocopy, LOD = 0.6. Including Harvard LMM there is conflicting data and best LOD is .15.

See Andersen PS et al. 2001 (11748309), Hougs L et al. 2005 (15483641), unpublished research (below).

 
Clinical importance
Severity 4

Potentially lethal, can cause sudden cardiac death.

Treatability 3

Surveillance, medical, and in some instances, surgical, intervention reduces the risk of sudden cardiac death.

Penetrance 4

HCM in carrier relatives is around 40% according to Michels et al. (PMID:19666645)

 

Impact

High clinical importance, Uncertain pathogenic

(The "high clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

dominant

Summary of published research, and additional commentary

The A13T variant has been reported in the literature (Poetter 1996, Szczesna 2001, Andersen 2001, Szczesna-Cordary 2004, Hougs 2005) but there is conflicting evidence regarding its pathogenicity. The variant was identified in two HCM probands as well as two affected family members and the variant was absent from at least 678 control chromosomes tested across both studies (Poetter 1996, Andersen 2001, Hougs 2005). However, this variant was not detected in one affected individual in the Anderson/Hougs family, raising some question as to whether it is the causative variant in the family. Later the authors identified a second variant, N1327K in MYH7, and proposed that this family had two mutations segregating. However, we have since accumulated enough data to suggest that N1327K is not disease-causing. While there is a possibility that the non-segregating family member has disease due to an environmental etiology (obesity and hypertension were noted), there is also the possibility that a third variant is actually responsible for disease (Hougs 2005). Functional studies examining effects of this mutation on protein function were not conclusive (Szczesna 2001, Szczesna-Cordary 2004).

Harvard LMM has also identified the A13T variant in another family; however, the variant only segregated with disease in 2/3 individuals. This data cannot be used in case/control statistics as the total number of individuals with hypertrophic cardiomyopathy screened by LMM for mutations in this gene is unavailable.

This variant is seen in a PGP participant (hu04FD18) who is healthy, had a normal cardiac evaluation, and no family history of heart disease. It should also be noted that most, if not all, of the individuals with the A13T variant are of Ashkenazi Jewish ancestry, and a screen of 116 healthly Ashkenazi Jewish controls was negative for the variant. In summary, the lack of segregation of the variant with disease in two affected individuals in the two families studied suggests that the variant may not be disease-causing; however, a conclusion cannot be made with certainty at this point.

HCM is not 100% penetrance, so a single healthy observation is insufficient to prove this variant is not pathogenic. However, observations reported to date lack statistical significance. Observations of PGP + public genomes used by GET-Evidence are combined with Ashkenazi Jewish controls for the control numbers used in the unpublished case/controls.

See also: http://genepath.med.harvard.edu/seidman//cg3/muts/MYL2_Ala13Thr.html

Total cases/controls case+ case– control+ control– p-value odds ratio
Familial Hypertrophic Cardiomyopathy
2 595 0 339 0.5375

 

Allele frequency

  • T @ chr12:111356964: 0.0% (2/10758) in EVS
  • T @ chr12:109841346: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.0% (2/10758)

Publications
 

Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND. 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. PubMed PMID: 8673105.

399 unrelated individuals with hypertrophic cardiomyopathy were screened for mutations in MYL2 (called “regulatory light chain”, RLC). One individual with this variant was found, as well as three other individuals with two other missense variants. A screen of the same regions in 189 control individuals found no variants. Although the ethnicity of the individuals was not mentioned, the main authors of the study were based in Bethesda, Maryland.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Hypertrophic Cardiomyopathy
1 398 0 189 1.0000

 

Szczesna D, Ghosh D, Li Q, Gomes AV, Guzman G, Arana C, Zhi G, Stull JT, Potter JD. Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation. J Biol Chem. 2001 Mar 9;276(10):7086-92. Epub 2000 Dec 1. PubMed PMID: 11102452.

In this biochemical study the effects of five different substitutions in MYL2 (called RLC here) were studied, including the A13T variant. In the wild-type protein, calcium ion binding affinity is reduced ~7-fold when the protein is phosphorylated. The unphosphorylated A13T variant was observed to have slightly reduced binding affinity to Ca2+ relative to unphosphorylated wild-type (~3-fold). When phosphorylated, the variant actually increased binding affinity, resulting in a binding affinity ~17-fold higher than phosphorylated wild type. Additionally, there is a conformational change with this residue change.

Andersen PS, Havndrup O, Bundgaard H, Moolman-Smook JC, Larsen LA, Mogensen J, Brink PA, Børglum AD, Corfield VA, Kjeldsen K, Vuust J, Christiansen M. Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations. J Med Genet. 2001 Dec;38(12):E43. PubMed PMID: 11748309; PubMed Central PMCID: PMC1734772.

Found in two siblings from a Danish kindred presenting HCM. A third sibling is reported as a phenocopy due to severe obesity and hypertension. The variant was absent from 150 controls and 197 additional probands. Excluding the phenocopy this has a LOD = 0.6. If the putative phenocopy is included, max LOD = 0.07 with theta = 0.33.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Hypertrophic Cardiomyopathy
1 197 0 150 1.0000

 

Roopnarine O. Mechanical defects of muscle fibers with myosin light chain mutants that cause cardiomyopathy. Biophys J. 2003 Apr;84(4):2440-9. PubMed PMID: 12668451; PubMed Central PMCID: PMC1302809.

This variant led to decreased sensitivity to Ca levels in rabbit psoas fibers.

Szczesna-Cordary D, Guzman G, Ng SS, Zhao J. Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction. J Biol Chem. 2004 Jan 30;279(5):3535-42. Epub 2003 Nov 1. PubMed PMID: 14594949.

The Roopnarine et al. finding is replicated in porcine cardiac myofibril. This variant is conserved in pig but not in mouse or rat.

Hougs L, Havndrup O, Bundgaard H, Køber L, Vuust J, Larsen LA, Christiansen M, Andersen PS. One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations [corrected] in MYH7 rod region. Eur J Hum Genet. 2005 Feb;13(2):161-5. Erratum in: Eur J Hum Genet. 2005 May;13(5):694. PubMed PMID: 15483641.

In a re-analysis of the family presented in (PMID 11748309) an additional potentially causative variant, MYH7 Asn1327Lys, was found in one of the above affected individuals and in the phenocopy.

Genomes
 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het T @ chr12:111356964

The variant was confirmed in a CLIA laboratory. He was referred to a cardiologist where he received a baseline echocardiogram. The echocardiogram was normal.

Other external references
 

    dbSNP
  • rs104894363
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the MYL2 gene
    Familial Hypertrophic Cardiomyopathy
    MYL2-Related Familial Hypertrophic Cardiomyopathy
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MYL2
    Web search results (44 hits -- see all)
  • European Journal of Human Genetics - One third of Danish ...
    Screening of this proband in the MYL2 gene had previously identified an A13T mutation.10 Others have shown this mutation to be disease-associated. ...
    www.nature.com/ejhg/journal/v13/n2/full/5201310a.html
  • Mendelian Inheritance in Man Document Reader
    Although the precise role of MYL2 in cardiac muscle is not well understood, an ... (1996) identified an ala13-to-thr (A13T) mutation in the MYL2 gene. ...
    www.angis.org.au/bin/Databases/BIRX/birx_doc?phtomim+160781
  • Research Appreciation Day - View Abstract
    STUDY OF CROSS BRIDGE KINETICS IN A13T MUTANT MOUSE HEART ... (FHC) is the A13T point mutation in the ventricular myosin regulatory light chain (RLC) encoded by the MYL2 gene. ...
    www.hsc.unt.edu/RAD/abstracts/viewabstract.cfm?ID=403
  • feature table
    ... 7357..7435,7537..7585,9506..9601) FT /note=MYL2 FT mutation 1521 FT /label="A13T" FT /note="Ala13Thr, G>A" FT mutation ...
    genepath.med.harvard.edu/~seidman/cg3/.../MYL2_features.txt
  • Mechanical Defects of Muscle Fibers with Myosin Light Chain ...
    A13T and E22K result in a rare myopathy in the heart (midventricular chamber thickening) ... regulatory myosin light chain gene (MYL2) associated with familial ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • FHC Mutation Database : Query Results
    MYL2. exon 2. c. 67G>A. A13T. confirmed. Poetter K / Epstein ND, et al. Nature Genet 1996 13: ... MYL2. exon 3. c. 171C>A. N47K. confirmed. Andersen PS / Christiansen M, et ...
    www.angis.org.au/pbin/Databases/Heart/fhcquery.cgi
  • Familial Hypertrophic Cardiomyopathy : From Mutations to ...
    MYL2 is located on chromosome 12q23-q24.3,67 and we have recently refined its ... them (E22K and A13T) are associated with the same rare phenotype seen with ...
    circres.ahajournals.org/cgi/content/full/83/6/580

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 5

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