NM_001276345.2(TNNT2):c.412-6_412-4del AND not specified

Germline classification:: Benign/Likely benign (2 submissions)
Last evaluated:: Jun 12, 2023
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:: RCV000036582.6

Allele description [Variation Report for NM_001276345.2(TNNT2):c.412-6_412-4del]

NM_001276345.2(TNNT2):c.412-6_412-4del

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1q32.1

Genomic location:

Preferred name:

NM_001276345.2(TNNT2):c.412-6_412-4del

HGVS:

NC_000001.10:g.201333507_201333509del
NC_000001.11:g.201364381_201364383del
NG_007556.1:g.18297_18299del
NM_000364.4:c.412-6_412-4del
NM_001001430.3:c.382-6_382-4del
NM_001001431.3:c.382-6_382-4del
NM_001001432.3:c.367-6_367-4del
NM_001276345.2:c.412-6_412-4delMANE SELECT
NM_001276346.2:c.292-6_292-4del
NM_001276347.2:c.382-6_382-4del
LRG_431t1:c.412-6_412-4del
LRG_431:g.18297_18299del
NC_000001.10:g.201333507_201333509del
NC_000001.10:g.201333507_201333509delAGG
NC_000001.10:g.201333509_201333511del
NM_001001430.1:c.382-6_382-4del
NM_001001430.1:c.382-6_382-4delCCT
NM_001001430.2:c.382-6_382-4del
NM_001001430.2:c.382-6_382-4delCCT
c.382-6_382-4delCCT

Links:

dbSNP: rs397516462

NCBI 1000 Genomes Browser:

rs397516462

Molecular consequence:

NM_000364.4:c.412-6_412-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001001430.3:c.382-6_382-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001001431.3:c.382-6_382-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001001432.3:c.367-6_367-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001276345.2:c.412-6_412-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001276346.2:c.292-6_292-4del - intron variant - [Sequence Ontology: SO:0001627]
NM_001276347.2:c.382-6_382-4del - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060237	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Nov 9, 2010)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004020748	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jun 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22464770, 24503780 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060237

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Nov 9, 2010)

germline

clinical testing

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

SCV004020748

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Jun 12, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	2	2	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

Genetic testing for dilated cardiomyopathy in clinical practice.

Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP, Johnson N, Mendelsohn NJ, Morel C, Care M, Chung WK, Jones C, Psychogios A, Duffy E, Rehm HL, White E, Seidman JG, Seidman CE, Ho CY.

J Card Fail. 2012 Apr;18(4):296-303. doi: 10.1016/j.cardfail.2012.01.013. Epub 2012 Feb 15.

PubMed [citation]

PMID:: 22464770
PMCID:: PMC3666099

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060237.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

The 382-6_382-4delCCT variant has not been reported in the literature but has be en detected by our laboratory in two Asian probands, one with HCM and one with D CM. The HCM case already had another variant thought to be causative for disease . In silico tools do not predict an impact to the splicing consensus sequence. I n summary, this data suggests this variant is likely benign.

#	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		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020748.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: TNNT2 c.382-6_382-4delCCT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 249246 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNNT2 causing Cardiomyopathy phenotype (0.00018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.382-6_382-4delCCT has been reported in the literature in individuals affected with Cardiomyopathy (Lakdawala_2012 and Pugh_2014) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 22464770). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

#	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

Last Updated: Sep 29, 2024

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