ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.641_643AGA[3] (p.Lys217del) (rs45578238)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000247384 SCV000320613 pathogenic Cardiovascular phenotype 2017-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses)
GeneDx RCV000223828 SCV000209279 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing The c.629_631delAGA pathogenic variant in the TNNT2 gene has previously been published multiple times in association with DCM and has been shown to segregate with disease in multiple unrelated families (Kamisago et al., 2000; Hanson et al., 2002; Mogensen et al., 2004; Venkatraman et al., 2003; Hershberger et al., 2009; Sfichi-Duke et al., 2010; Otten et al., 2010; Pugh et al., 2014). 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 70's. However, of the 13 affected individuals identified in the family, 10 had onset of features before 30 years of age (Hanson et al., 2002). Similarly, Mogensen et al. (2004) reported c.629_631delAGA in four members of one family who had severe DCM necessitating heart transplantation or leading to cardiac death in the second or third decade of life. This variant has also been observed in multiple other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to have occurred de novo in at least two individuals. The c.629_631delAGA pathogenic variant results in an in-frame deletion resulting in the loss of one of four consecutive lysine residues in the calcium-sensitive troponin-C binding domain of cardiac troponin T. Functional studies revealed that 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). Furthermore, the c.629_631delAGA variant is not observed in large population cohorts (Lek et al., 2016). In summary, c.629_631delAGA in the TNNT2 gene is interpreted as a pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000036607 SCV000840076 pathogenic Left ventricular noncompaction 6 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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000524543 SCV000541926 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-10-25 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 13 of the TNNT2 mRNA (c.629_631delAGA). This leads to the deletion of 1 amino acid residue in the TNNT2 protein (p.Lys210del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs45578238, ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy in several families (PMID: 11106718, 20978592). This variant has also been shown to arise de novo in individuals affected with dilated cardiomyopathy (PMID: 20978592). This variant is also known as p.K217del in the literature. ClinVar contains an entry for this variant (Variation ID: 43659). Experimental studies have shown that this missense change has a deleterious effect on TNNT2 activity (PMID: 11773635, 12186860, 12923187, 15623536, 23383212, 23663841, 20079745, 22675533, 17932326, 15923195, 23539503). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.
OMIM RCV000036607 SCV000033471 pathogenic Left ventricular noncompaction 6 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.

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