NM_001276345.2(TNNT2):c.354_355delinsGT (p.His119Tyr) AND Primary dilated cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 16, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000220636.5

Allele description [Variation Report for NM_001276345.2(TNNT2):c.354_355delinsGT (p.His119Tyr)]

NM_001276345.2(TNNT2):c.354_355delinsGT (p.His119Tyr)

Gene:

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

Variant type:

Indel

Cytogenetic location:

1q32.1

Genomic location:

Preferred name:

NM_001276345.2(TNNT2):c.354_355delinsGT (p.His119Tyr)

HGVS:

NC_000001.11:g.201365247_201365248delinsAC
NG_007556.1:g.17430_17431delinsGT
NM_000364.4:c.354_355delinsGT
NM_001001430.3:c.324_325delinsGT
NM_001001431.3:c.324_325delinsGT
NM_001001432.3:c.309_310delinsGT
NM_001276345.2:c.354_355delinsGTMANE SELECT
NM_001276346.2:c.291+362_291+363delinsGT
NM_001276347.2:c.324_325delinsGT
NP_000355.2:p.His119Tyr
NP_001001430.1:p.His109Tyr
NP_001001431.1:p.His109Tyr
NP_001001432.1:p.His104Tyr
NP_001263274.1:p.His119Tyr
NP_001263276.1:p.His109Tyr
LRG_431t1:c.354_355delinsGT
LRG_431:g.17430_17431delinsGT
LRG_431p1:p.His119Tyr
NC_000001.10:g.201334375_201334376delinsAC

Protein change:

H104Y

Links:

dbSNP: rs876658027

NCBI 1000 Genomes Browser:

rs876658027

Molecular consequence:

NM_001276346.2:c.291+362_291+363delinsGT - intron variant - [Sequence Ontology: SO:0001627]
NM_000364.4:c.354_355delinsGT - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.324_325delinsGT - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.324_325delinsGT - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.309_310delinsGT - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.354_355delinsGT - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.324_325delinsGT - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Primary dilated cardiomyopathy (DCM)
Synonyms:: Dilated Cardiomyopathy
Identifiers:: EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000272527	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Nov 16, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272527

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Nov 16, 2017)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272527.3

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

Description

The c.324_325delinsGT (p.His109Tyr) variant in TNNT2 has not been reported in an y other individuals with cardiomyopathy, however another variant (c.325C>T) resu lting in the same amino acid change (p.His109Tyr) was identified by our laborato ry in one individual with early onset DCM, ventricular tachycardia and a family history of HCM and sudden death (Pugh 2014). Both variants are absent in large population databases. Parental testing for the c.324_325delinGT variant was nega tive indicating that the variant occurred de novo in this individual. In additio n, the histidine residue (His) at position 109 is highly conserved in mammals an d across evolutionary distant species and the change to amino acid Tyrosine (Tyr ) at this position is predicted to be pathogenic using a computational tool clin ically validated by our laboratory (Jordan 2011). In summary, although additiona l studies are required to fully establish its clinical significance, the p.His10 9Tyr variant is likely pathogenic. ACMG/AMP Criteria applied: PS2; PM2; PP3.

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

Last Updated: Apr 6, 2024

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