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

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 8, 2024
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:
RCV000211867.10

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:
13

Condition(s)

Name:
Hypertrophic cardiomyopathy
Synonyms:
HYPERTROPHIC MYOCARDIOPATHY
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000060251Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Oct 8, 2012) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV004839106All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 8, 2024) 		germlineclinical testing

PubMed (20)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided2113not providednot providednot providedclinical testing
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region.

Palm T, Graboski S, Hitchcock-DeGregori SE, Greenfield NJ.

Biophys J. 2001 Nov;81(5):2827-37. Erratum in: Biophys J 2002 May;82(5):2826.

PubMed [citation]
PMID:
11606294
PMCID:
PMC1301748

Comparison of fluorescent SSCP and denaturing HPLC analysis with direct sequencing for mutation screening in hypertrophic cardiomyopathy.

Mogensen J, Bahl A, Kubo T, Elanko N, Taylor R, McKenna WJ.

J Med Genet. 2003 May;40(5):e59. No abstract available.

PubMed [citation]
PMID:
12746413
PMCID:
PMC1735481
See all PubMed Citations (25)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060251.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided21not providednot providedclinical testing PubMed (9)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided21not provided13not provided

From All of Us Research Program, National Institutes of Health, SCV004839106.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (20)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024