Variant rs45578238 details in Genebe, Genetics Data Aggregator

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

TNNT2 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001276345.2. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-201361970-ATCT-A is Pathogenic according to our data. Variant chr1-201361970-ATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201361970-ATCT-A is described in Lovd as [Pathogenic]. Variant chr1-201361970-ATCT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.659_661del	p.Lys220del	inframe_deletion	14/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.659_661del	p.Lys220del	inframe_deletion	14/17		NM_001276345.2	A2	P45379-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461878

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

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0.00

Gnomad4 AMR exome

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Gnomad4 ASJ exome

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0.00

Gnomad4 EAS exome

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0.00

Gnomad4 SAS exome

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0.00

Gnomad4 FIN exome

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0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

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0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2022	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 (gnomAD); 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: 31983221, 32458740, 30847666, 31447099, 28436080, 28839205, 34298581, 17932326, 12923187, 15623536, 15923195, 14654368, 20079745, 20978592, 22675533, 23383212, 11773635, 12186860, 23663841, 26178429, 24503780, 26688388, 11106718, 11862580, 15542288, 20031601, 27532257, 29212898, 29447731, 31112419, 31514951, 31918855, 32160020, 23539503, 32563186, 33662488, 31251381, 34426522, 33906374, 33941202, 27535533, 32581830, 33025817) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 05, 2021	PP1_strong, PS3, PS4, PM2, PM4, PM6 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 18, 2012	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, Venkat -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dilated cardiomyopathy 1D

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	KTest Genetics, KTest	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 06, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 16, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss of function, gain of function and dominant negative mechanisms based on calcium sensitivity, contractibility and mouse models. Although it is important to note that ClinGen has concluded that there is no evidence for haploinsufficiency for this gene (PMID: 18612386, 32098556, 33025817; ClinGen). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. p.(Arg92Gln) has been described in families which have both DCM and HCM (PMID: 26507537). (I) 0214 - In-frame deletion fully contained in a repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated troponin domain (NCBI, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than 30 probands with DCM and as been classified as pathogenic by diagnostic laboratories in ClinVar. (PMID: 20978592, 24503780; ClinVar). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Primary dilated cardiomyopathy

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	research	Klaassen Lab, Charite University Medicine Berlin	Jul 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 24, 2021	The p.Lys210del variant in TNNT2 has been reported in multiple families with DCM and segregated with disease in >10 affected relatives (Kamisago 2000 PMID: 11106718, Hanson 2002 PMID: 11862580, Mogensen 2004 PMID: 15542288, Hershberger 2009 PMID: 20031601, Otten 2010 PMID: 20978592, LMM data). This variant has been classified as Pathogenic by multiple laboratories in ClinVar (Variation ID 43659). It was absent from large population studies. Multiple functional studies support a disease-causing role (Venkatraman 2003 PMID: 12923187, Venkatraman 2005 PMID: 15623536, Ahmad 2008 PMID: 18612386, Sfichi-Duke 2010 PMID: 20079745, Liu 2012 PMID: 22675533, Sugihara 2013 PMID: 23383212). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 05, 2019	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]. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant causes an in-frame deletion of one amino acid in the troponin C binding domain of the TNNT2 protein. Experimental functional studies using rabbit cardiac muscle fibers have shown that this variant causes a disruption to calcium sensitivity (PMID: 11773635, 12923187, 15623536, 15923195). Recombinant human troponin complexes expressing this variant have shown that this variant causes decreased filament mobility (PMID: 12186860, 15923195). Additionally, a mouse model for this variant has shown a recapitulation of the human dilated cardiomyopathy phenotype, including cardiac enlargement, heart failure and sudden death (PMID: 17556660). This variant has been reported in over 20 unrelated individuals affected with dilated cardiomyopathy (PMID: 11106718, 11862580, 14567970, 15542288, 20031601, 20978592, 22949430, 24503780, 25179549, 31568572). It has been shown that this variant segregates with disease in multiple affected individuals across at least 10 families (PMID: 11106718, 15542288, 20031601, 20978592, 25179549). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 29212898). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -

Cardiovascular phenotype

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2022	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 in 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2017	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. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 22, 2019

- -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

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. ClinVar contains an entry for this variant (Variation ID: 43659). 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. -

Computational scores

Source: dbNSFP v4.3

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SpliceAI score (max)

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Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs45578238

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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