NM_000363.5(TNNI3):c.356C>A (p.Thr119Asn) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 25, 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:: RCV000788296.18

Allele description [Variation Report for NM_000363.5(TNNI3):c.356C>A (p.Thr119Asn)]

NM_000363.5(TNNI3):c.356C>A (p.Thr119Asn)

Gene:

TNNI3:troponin I3, cardiac type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.42

Genomic location:

Preferred name:

NM_000363.5(TNNI3):c.356C>A (p.Thr119Asn)

HGVS:

NC_000019.10:g.55154757G>T
NG_007866.2:g.7976C>A
NM_000363.5:c.356C>AMANE SELECT
NP_000354.4:p.Thr119Asn
LRG_432t1:c.356C>A
LRG_432:g.7976C>A
NC_000019.9:g.55666125G>T
NM_000363.4:c.356C>A
c.356C>A

Protein change:

T119N

Links:

dbSNP: rs184709702

NCBI 1000 Genomes Browser:

rs184709702

Molecular consequence:

NM_000363.5:c.356C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000927353	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Uncertain significance (Jul 21, 2017)	germline	clinical testing	Citation Link,
SCV001471608	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Aug 23, 2020)	germline	clinical testing	Citation Link,
SCV001831876	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 25, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000927353

Blueprint Genetics

criteria provided, single submitter

(Blueprint Genetics Variant Classification Scheme)

Uncertain significance
(Jul 21, 2017)

germline

clinical testing

Citation Link,

SCV001471608

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Aug 23, 2020)

germline

clinical testing

Citation Link,

SCV001831876

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Nov 25, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From Blueprint Genetics, SCV000927353.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471608.1

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

Description

The TNNI3 c.356C>A; p.Thr119Asn variant (rs184709702) is reported in the literature in cohort studies of patients affected with dilated and hypertrophic cardiomyopathies (Walsh 2017 and Coppini 2014). This variant is also reported to the ClinVar database as uncertain (Variation ID: 43375). It is also found in the general population with an overall allele frequency of 0.003% (10/280,786 alleles) in the Genome Aggregation Database. The threonine at codon 119 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr119Asn variant is uncertain at this time. References: Coppini et al. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol. 2014 Dec 23. Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb. Gene statement: Pathogenic variants in TNNI3 are associated with autosomal dominant hypertrophic cardiomyopathy 7 (MIM: 613690), familial restrictive cardiomyopathy 1 (MIM: 115210), dilated cardiomyopathy 1FF (MIM: 613286), and autosomal recessive dilated cardiomyopathy 2A (MIM: 611880).

#	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 GeneDx, SCV001831876.2

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

Description

Reported in individuals with DCM and HCM referred for genetic testing at GeneDx and in published literature (Lakdawala et al., 2012; Coppini et al., 2014; Pugh et al., 2014; Wang et al., 2016; Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26169204, 27532257, 24503780, 26440512, 22464770, 25524337)

#	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

Last Updated: Jun 23, 2024

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