rs397516470
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_001276345.2(TNNT2):βc.517_519delβ(p.Glu173del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. E173E) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
TNNT2
NM_001276345.2 inframe_deletion
NM_001276345.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.74
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001276345.2
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-201363376-TCTC-T is Pathogenic according to our data. Variant chr1-201363376-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201363376-TCTC-T is described in Lovd as [Likely_pathogenic]. Variant chr1-201363376-TCTC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNT2 | NM_001276345.2 | c.517_519del | p.Glu173del | inframe_deletion | 12/17 | ENST00000656932.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNT2 | ENST00000656932.1 | c.517_519del | p.Glu173del | inframe_deletion | 12/17 | NM_001276345.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461872Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727240
GnomAD4 exome
AF:
AC:
2
AN:
1461872
Hom.:
AF XY:
AC XY:
2
AN XY:
727240
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
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 16, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies in E. coli demonstrated p.(E163del) (reported as deltaE160) resulted in recombinant troponin with increased calcium ion sensitivity (Messer et al., 2016); Published functional studies using transgenic mice demonstrated that the del160E (c.487_489delGAG) variant leads to cellular hypertrophy and myofilament disarray as well as impairments in contraction, relaxation, and calcium handling (Moore et al., 2013; Moore et al., 2014); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14654368, 22579624, 22144547, 7898523, 28771489, 12746413, 31589614, 33673806, 33025817, 21835320, 23054336, 20800588, 25558701, 12707239, 20624503, 24480310, 27662471, 27639548, 26688388, 16538283, 27532257, 28214152, 24792744, 26714042, 31006259, 31308319, 31387947, 22260945, 14636924, 11606294, 10731693, 33906374, 23434821, 27036851) - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 16, 2018 | - - |
Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 12, 2017 | Testing for our patients was performed at the Invitae laboratory. Given the strong case data, supportive functional studies, and absence in general population databases, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is also referenced in the literature as DeltaE160. The variant has been published in at least 8 unrelated cases of HCM and 3 unrelated cases of RCM (not including this patient's family). We have seen this variant in two patients with HCM at our center. Many of the published families have several affected family members who carry the variant. There is additional case data and strong segregation data have been reported by genetic testing laboratories. The unrelated case count is a conservative estimate, however it is difficult to discern independent cases since few of the published cases report where genetic testing was done and overlapping authors. Presumably some of the original cases published by Watkins in 1995 overlap with cases documented by testing laboratories. Watkins et al. (1995) first reports this variant in patients with HCM. They report the variant was observed in 32 individuals from two families (includes those identified by screening, those deduced from pedigree, and some deceased individuals). However, only 14 of those individuals were studied clinically. 14 of the 32 individuals died suddenly. Average maximum wall thickness was 17.5mm. Study was done at Harvard. Richard et al (2003) report this variant in one index patient with HCM (recruited in France). HCM diagnostic criteria for the study included wall thickness >1.3cm or major abnormalities on ECG. Torricelli et al (2003) reports the variant in three affected individuals of one family (proband, brother, nephew) with HCM. These individuals were recruited from Tuscany. Millat et al. (2010) report this variant in one affected proband with HCM. Patients were French. While possibly an overlapping case with Richard et al, the authors do not appear to overlap. Pasquale et al (2012) refers to the variant as Delta163. The authors observed the variant in 3 families, with 27 carriers. Cases may overlap with those from Watkins et al. There was no specific clinical data for the individuals with the variant, although they all had HCM. Walsh et al. (2012) report this variant in a proband with RCM diagnosed at 17yo and another with RCM diagnosed at 16yo. Maron et al (2014) reports this variant in a brief case report of a family with HCM and RCM (see pedigree below). The authors report that this variant was associated with several phenotypes: non-dilated LV with segmental hypertrophy (no measurements) and intact systolic function, end stage HCM with LV remodeling and systolic dysfunction, and "restrictive" form with impaired ejection fraction. Individual III-4 had non obstructive HCM, anterior ventricular septum measuring 2.3cm, and EF 53% at 37yo. Individual III-2 had non obstructive HCM, posterior ventricular septum measuring 2.1cm and EF of 75% at 28yo. Individual II-1 had a progressive heart failure requiring transplantation at 54yo. He also had history of 2 cardiac arrests, EF of 30% and LVEDD of 5.2cm. Individual II-5 is a 67yo with heart failure requiring transplantation at age 61. She had a restrictive phenotype, LV wall was normal thickness, and EF of 40%. It is unclear from the pedigree if these individuals are all from one family or separate families. The authors also do not include clinical information on those individuals who have tested negative (II-6, III-5, and III-6). The glutamine at codon 163 is conserved across species. The variant falls within the hinge-flexible loop domain and several functional studies have been done to investigate the functional effect of this single amino acid deletion. Harada et al. (2000) report that "the mutant troponin T showed a slightly reduced potency in replaci - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Nov 28, 2016 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | May 28, 2021 | - - |
Hypertrophic cardiomyopathy Pathogenic:2
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 at exon 11 of the tropomyosin binding domain 1 in the TNNT2 protein. In-vivo functional studies using a transgenic mouse knock-in model have shown that this variant causes a phenotype consistent with hypertrophic cardiomyopathy, including sarcomeric abnormalities, cellular hypertrophy, decreased calcium uptake activity, and myofilament disarray (PMID: 23434821, 24480310, 26714042). Additional in-vitro functional studies using transfected porcine cardiac myofibrils have shown that this variant causes altered troponin affinity and increased calcium sensitivity (PMID: 10731693) . This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 12707239, 14636924, 20800588, 21835320, 22144547, 24792744, 25611685, 27639548, 28771489, 28790153, 27532257, 31308319, 33029862, 33673806). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 7898523, 14636924). This variant has been reported to occur de novo in one individual affected with hypertrophic cardiomyopathy (PMID: 25611685). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 08, 2012 | The p.Glu163del variant in TNNT2 has been previously reported in multiple famili es with HCM, segregated with disease in >10 affected family members, and was abs ent from 700 control chromosomes (Watkins 1995, Palm 2001, Richard 2003, Torrice lli 2003, LMM unpublished data). Functional studies indicate that this variant m ay impact protein function (Tobacman 1999, Harada 2000, Manning 2012), though th ese in vitro assays may not accurately represent biological function. In summary , this variant meets our criteria to be classified as pathogenic for HCM in an a utosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) base d on segregation studies and absence from controls. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 28, 2021 | The c.487_489delGAG pathogenic mutation (also known as p.E163del) is located in coding exon 10 of the TNNT2 gene. This alteration results from an in-frame deletion of 3 nucleotides at positions 487 to 489, causing the removal of a well-conserved glutamic acid residue at codon 163. Strong segregation of this alteration, also described as ΔGlu160, with hypertrophic cardiomyopathy has been demonstrated (Watkins H et al. N Engl J Med. 1995;332(16):1058-64). This alteration has also been detected in patients reported to have restrictive cardiomyopathy (Walsh MA et al. Circ Heart Fail. 2012;5(2):267-73). Additionally, a combination of in vitro and in vivo studies showed disrupted weak electrostatic actomyosin binding in motility assays and severe cardiac remodeling and myofilament disarray in transgenic mice (Moore RK et al. Arch Biochem Biophys. 2014;552-553:21-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Hypertrophic cardiomyopathy 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Cardiology unit, Meyer University Hospital | Sep 27, 2022 | - - |
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This variant, c.487_489del, results in the deletion of 1 amino acid(s) of the TNNT2 protein (p.Glu163del), 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 individuals with hypertrophic cardiomyopathy (HCM) and restricted cardiomyopathy (RCM) (PMID: 7898523, 20624503, 22144547, 22260945, 24792744). It has also been observed to segregate with disease in related individuals. This variant is also known as DeltaE160. ClinVar contains an entry for this variant (Variation ID: 43648). 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: 10731693, 22579624, 24480310, 27036851). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at