NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: May 16, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000624557.12

Allele description [Variation Report for NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del)]

NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del)

Gene:

TNNT2:troponin T2, cardiac type [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

1q32.1

Genomic location:

Preferred name:

NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del)

HGVS:

NC_000001.10:g.201332505_201332507del
NC_000001.11:g.201363377CTC[3]
NG_007556.1:g.19290GAG[3]
NM_000364.4:c.508GAG[3]
NM_001001430.3:c.478GAG[3]
NM_001001431.3:c.478GAG[3]
NM_001001432.3:c.463GAG[3]
NM_001276345.2:c.508GAG[3]MANE SELECT
NM_001276346.2:c.388GAG[3]
NM_001276347.2:c.478GAG[3]
NP_000355.2:p.Glu173del
NP_001001430.1:p.Glu163del
NP_001001431.1:p.Glu163del
NP_001001432.1:p.Glu158del
NP_001263274.1:p.Glu173del
NP_001263275.1:p.Glu133del
NP_001263276.1:p.Glu163del
LRG_431t1:c.508GAG[3]
LRG_431:g.19290GAG[3]
LRG_431p1:p.Glu173del
NC_000001.10:g.201332505CTC[3]
NC_000001.10:g.201332505_201332507del
NC_000001.10:g.201332505_201332507delCTC
NC_000001.10:g.201332514_201332516del
NM_000364.2:c.517_519del
NM_000364.3:c.517_519delGAG
NM_001001430.1:c.487_489del
NM_001001430.1:c.487_489delGAG
NM_001001430.2:c.487_489del
NM_001001430.2:c.487_489delGAG
c.487_489delGAG

Protein change:

E133del

Links:

dbSNP: rs397516470

NCBI 1000 Genomes Browser:

rs397516470

Molecular consequence:

NM_000364.4:c.508GAG[3] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001001430.3:c.478GAG[3] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001001431.3:c.478GAG[3] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001001432.3:c.463GAG[3] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001276345.2:c.508GAG[3] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001276346.2:c.388GAG[3] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001276347.2:c.478GAG[3] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209278	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 16, 2022)	germline	clinical testing	Citation Link,
SCV000740431	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 28, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000924966	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Apr 12, 2017)	germline	provider interpretation
SCV000927600	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Mar 16, 2018)	germline	clinical testing	Citation Link,
SCV001929709	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001953581	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002501176	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 28, 2021)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 7898523, 31387947, 26714042, 27662471, 14654368, 22579624, 24792744, 27036851, 24480310, 23434821, 31006259, 27532257, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	provider interpretation

Citations

PubMed

Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.

Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG, et al.

N Engl J Med. 1995 Apr 20;332(16):1058-64.

PubMed [citation]

PMID:: 7898523

FRET-based analysis of the cardiac troponin T linker region reveals the structural basis of the hypertrophic cardiomyopathy-causing Δ160E mutation.

Abdullah S, Lynn ML, McConnell MT, Klass MM, Baldo AP, Schwartz SD, Tardiff JC.

J Biol Chem. 2019 Oct 4;294(40):14634-14647. doi: 10.1074/jbc.RA118.005098. Epub 2019 Aug 6.

PubMed [citation]

PMID:: 31387947
PMCID:: PMC6779437

See all PubMed Citations (13)

Details of each submission

From GeneDx, SCV000209278.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000740431.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000924966.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

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 replacing the endogenous troponin complex in myofibrils and did not affect the inhibitory action of troponin I but potentiated the neutralizing action of troponin C, suggesting that the deletion of a single amino acid, Glu-160, in the strong tropomyosin-binding region affects the tropomyosin binding affinity of the entire troponin T molecule and alters the interaction between troponin I and troponin C within ternary troponin complex in the thin filament. This mutation also increased the Ca(2+) sensitivity of the myofibrillar ATPase activity, as in the case of other mutations in troponin T with clinical phenotypes of poor prognosis similar to that of Glu160." Manning et al (2012) found that this variant results in a decrease in flexibility of the troponin T protein, which results in a tightening of the helix at the C-terminus of TNT1 that both stiffens TNT1 and pulls on the cTnT linker. This results in dramatically different physical behavior. Moore et al (2014) evaluated the in vivo effects of this variant in mutant mice. Severe, progressive cardiac remodeling and myofilament disarray were observed in vivo. In vitro motility assays were consistent with weaker electrostatic binding conditions and increased calcium sensitivity. Messer et al (2016) also replicated increased calcium sensitivity in vitro in troponin T protein harboring this variant. The variant is not present in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >123,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 95x.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Blueprint Genetics, SCV000927600.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001929709.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001953581.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002501176.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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