rs397516470

Positions:

• chr1-201363376-TCTC-T
• chr1-201363376-TCTC-TCTCCTC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.517_519del​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. E173E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• 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]

ACMG classification

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs397516470; hg19: chr1-201332504;