ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.650AGA[3] (p.Lys220del)

dbSNP: rs45578238
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000211868 SCV000060262 pathogenic Primary dilated cardiomyopathy 2017-11-22 criteria provided, single submitter clinical testing The p.Lys210del variant in TNNT2 has been reported in multiple families with DCM and segregated with disease in >10 affected relatives (Kamisago 2000, Hanson 20 02, Mogensen 2004, Hershberger 2009, Otten 2010, LMM data). It has not been iden tified in large population studies. In addition, multiple functional studies sup port a disease-causing role (Venkatraman 2003, Venkatraman 2005, Ahmad 2008, Sfi chi-Duke 2010, Liu 2012, Sugihara 2013). In summary, this variant meets criteria to be classified as pathogenic based upon segregation studies, absence from con trols, and functional evidence. ACMG/AMP criteria applied: PS4, PP1_VeryStrong, PS3.
GeneDx RCV000223828 SCV000209279 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing Hanson et al. (2002) identified c.629_631delAGA in one family with DCM with phenotypes of affected family members ranging from severe, infantile onset to mild disease with onset in the 70s; however, of the 13 affected individuals identified in the family, 10 had onset of features before 30 years of age (Hanson et al., 2002); Not observed at significant frequency in large population cohorts (Lek 2006).; In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect; c.629_631delAGA causes a decrease in maximum speed of heart muscle contraction, leading to impaired systolic function and cardiac dilation (Mogensen et al., 2004; Venkatraman et al., 2003); This variant is associated with the following publications: (PMID: 27535533, 32563186, 23539503, 32160020, 31447099, 30847666, 32458740, 31983221, 31918855, 31514951, 31112419, 29447731, 29212898, 28839205, 28436080, 27532257, 20031601, 15542288, 11862580, 11106718, 26688388, 24503780, 26178429, 23663841, 12186860, 11773635, 23383212, 22675533, 20978592, 20079745, 14654368, 15923195, 15623536, 12923187, 17932326)
Ambry Genetics RCV000247384 SCV000320613 pathogenic Cardiovascular phenotype 2018-05-31 criteria provided, single submitter clinical testing The c.629_631delAGA pathogenic mutation (also known as p.K210del) is located in coding exon 12 of the TNNT2 gene. This alteration results from an in-frame AGA deletion between nucleotide positions 629 and 631. This results in the deletion of a lysine residue at codon 210. This alteration, also referred to as K217del, has been previously reported in multiple individuals and families with dilated cardiomyopathy (DCM). Phenotypic features, including DCM, sudden cardiac death, conduction system disease, and heart failure, were reported among individual patients and within and between families varying in age of onset, disease progression, and severity (Kamisago M et al. NEJM. 2000;343(23):1688-96). This alteration has also been reported to occur de novo, and has been detected cases with ventricular non-compaction (Otten E et al. Neth Heart J. 2010;18(10):478-85; Miller EM et al. Circ Cardiovasc Genet. 2017;10(6)). Functional in vitro analyses have reported this alteration to result in reduced cardiac contractile function (Morimoto S et al. PNAS. 2002;99(2):913-8; Venkatraman G et al. J Biol Chem. 2005;280(18):17584-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000524543 SCV000541926 pathogenic Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2021-11-22 criteria provided, single submitter clinical testing This variant, c.629_631del, results in the deletion of 1 amino acid(s) of the TNNT2 protein (p.Lys210del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 11106718, 20978592). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.K217del. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TNNT2 function (PMID: 11773635, 12186860, 12923187, 15623536, 15923195, 17932326, 20079745, 22675533, 23383212, 23539503, 23663841). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000247384 SCV000697567 pathogenic Cardiovascular phenotype 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The TNNT2 c.629_631delAGA (p.Lys210del) variant involves the deletion of three nucleotides, resulting in an in-frame deletion of a lysine residue. One in silico tool predicts a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/122292 control chromosomes). The variant has been identified in numerous patients with dilated cardiomyopathy (e.g., Walsh_GIM_2017) and segregates with disease in families (e.g., Kamisago_NEJM_2000). Functional studies have shown an aberrant response and sensitivity to calcium ions compared to WT (Robinson_JBC_2002; Morimoto_PNAS_2002). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000036607 SCV000840076 pathogenic Dilated cardiomyopathy 1D 2018-02-06 criteria provided, single submitter clinical testing The c.629_631delAGA (p.K210del) variant has been reported in multiple individuals with dilated cardiomyopathy (PMID: 1110678, 20978592, 15542288). In addition, experiential evidences has shown that the c.629_631delAGA (p.K210del) variant alters TNNT2 activity (PMID: 11773635, 12186860, 12923187, 14654368, 15623536). Therefore, we classify this variant as pathogenic.
Klaassen Lab,Charite University Medicine Berlin RCV000211868 SCV000995848 likely pathogenic Primary dilated cardiomyopathy 2019-07-03 criteria provided, single submitter research
New York Genome Center RCV000211868 SCV001441330 pathogenic Primary dilated cardiomyopathy 2019-06-05 criteria provided, single submitter clinical testing The de novo heterozygous 3-bps deletion removes one of the four consecutive Lysine residues from the calcium-sensitive troponin-C binding domain of troponin T. In the literature this variant is known as p.Lys210del, p.Lys217del, or p.Lys220del. It is a known recurrent pathogenic variant that has been reported in multiple unrelated patients as well as in large unrelated families segregating dilated cardiomyopathy [PMID: 11106718; PMID: 15542288; PMID: 20978592; PMID: 11862580]. This variant has also been reported to occur de novo in individuals affected with dilated cardiomyopathy[PMID: 20978592].
KTest Genetics,KTest RCV000036607 SCV001499977 pathogenic Dilated cardiomyopathy 1D criteria provided, single submitter clinical testing
Mayo Clinic Laboratories,Mayo Clinic RCV000223828 SCV001713932 pathogenic not provided 2020-02-26 criteria provided, single submitter clinical testing PP1_strong, PS3, PS4, PM2, PM4, PM6
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798105 SCV002042851 pathogenic Cardiomyopathy 2019-11-22 criteria provided, single submitter clinical testing
3billion RCV002051803 SCV002318468 pathogenic Hypertrophic cardiomyopathy 2 2022-03-22 criteria provided, single submitter clinical testing Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 1186258) and observed in multiple (>3) similarly affected unrelated individuals (PMID: 11862580, 27532257). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000043659, PMID:11106718). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000036607 SCV000033471 pathogenic Dilated cardiomyopathy 1D 2004-11-16 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223828 SCV000280531 pathogenic not provided 2012-01-18 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Lys210del (K210del; c.629_631delAGA) in the TNNT2 gene; heterozygous This well-studied variant was the first mutation in the human TNNT2 gene that was linked to familial DCM. It has been previously reported in at least 23 unrelated families with a diagnosis of dilated cardiomyopathy, with moderate segregation data available from multiple families as well as functional data and a mouse model (Kamisago et al. 2000, Morimoto et al. 2002, Robinson et al. 2002, Hanson et al. 2002, Venkatraman et al. 2003, Mogensen et al. 2004, Martins et al. 2006, Du et al. 2007, Hershberger et al. 2009, Sfichi-Duke et al. 2010, Otten et al. 2010, Pugh et al. 2014). Kamisago et al. (2000) found it in 2 unrelated families with DCM. In the first family, it segregated with disease in 3 affected family members across 2 meioses. In the other family it segregated in 3 affected family members across 3 meioses. Hanson et al. (2002) found it in an additional family with DCM, with no good segregation data. In these two studies, the phenotypes of affected family members ranged from severe infantile onset with sudden death to mild disease with death in their 60’s-70’s. However, multiple individuals with this variant died in infancy with confirmed cardiomyopathy, died in their teens following onset of congestive heart failure, or died suddenly in their mid-20s. The majority of affected individuals presented before 30 years of age. Phenotype variably included DCM, sudden cardiac death, atrial fibrillation, 1st-degree AV block, and heart failure. Sudden-onset, rapidly-progressive disease was observed in younger individuals. Mogensen et al. (2004) reported Lys210del segregating in 4 members of one family (3 meioses) with severe DCM necessitating heart transplantation or leading to cardiac death in the second or third decade of life. Martins et al. (2006) found Lys210del in 1 Portuguese family with an aggressive form of DCM, including sudden death or need for transplant in the third decade of life. Hershberger et al. (2009) found Lys210del in at least 3 additional Caucasian families with DCM. In one of those families it segregated with disease across 5 family members (and 4 meioses). Deaths in this family from DCM occurred at ages 1, 12, 16, and 21, with other affected family members living longer. Otten et al. (2010) found this variant in 4 Dutch families; among the 6 total living affected individuals, half of them required heart transplant at ages 12, 18, and 19 years. The 12-year old was a girl with a de novo Lys210del mutation. Mean age of disease manifestation was 33 years. Harvard’s Laboratory for Molecular Medicine has reported it in 11 unrelated probands tested for DCM (Pugh et al. 2014) and classifies it as pathogenic. It has also been observed in other unrelated individuals tested for DCM at GeneDx, according to the report. Lys210del is an in-frame deletion of one of four consecutive Lysine residues in the calcium-sensitive troponin-C binding domain of the cardiac troponin T protein. The Lysine at this location is not completely conserved across 10 vertebrate species sequenced (it is a methionine in X-tropicalis and a threonine in zebrafish). Other nearby variants (within 10 amino acids to either side) have been reported in association with DCM in HGMD: Arg205Leu, Arg205Trp. This variant has been functionally characterized and shown to cause a decrease in maximum speed of heart muscle contraction leading to impaired systolic function and cardiac dilation. The mutant protein has a reduced calcium sensitivity and requires higher free calcium concentrations for force generation and to activate ATPase (Morimoto et al. 2002, Robinson et al. 2002, Venkatraman et al. 2003). Mogensen et al. (2004) reported altered protein-protein interactions for the variant protein in a two-hybrid assay. Sfichi-Duke et al. (2010) showed that the variant alters posttranslational phosphorylation of key sarcomeric proteins. Du et al. (2007) created a mouse model with this variant and the mice developed enlarged hearts, heart failure, and high incidence of premature death. In total the variant has not been seen in ~6900 controls and individuals from publicly available population datasets. Most of these controls are ancestry-matched with our patient. (Our patient has Caucasian ancestry.) Kamisago et al. (2000) did not detect it in 200 healthy control individuals; Hanson et al. (2002, same group) did not add additional controls. Mogensen et al. (2004) did not detect it in 100 ethnically-matched controls nor in 760 individuals with HCM. Martins et al. (2006) did not find it in 100 controls, nor in 40 sporadic DCM cases. This variant is absent from the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on 4300 Caucasian and 2200 African-American individuals (as of July 23, 2014). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant is present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) as rs45578238, with the paper from Harvard’s Laboratory for Molecular Medicine as one of the references. There are no in-frame deletions in TNNT2 present in 1000 Genomes (http://browser.1000genomes.org). This deletion is absent from the ~60,000 individuals in ExAC as of 6/16/2015. ExAC contains only 1 individual with any in-frame deletion in TNNT2.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000223828 SCV001744062 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000223828 SCV001924002 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000223828 SCV001959425 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000223828 SCV001974839 pathogenic not provided no assertion criteria provided 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.