NM_000363.5(TNNI3):c.5C>T (p.Ala2Val) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 28, 2019
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:: RCV000036309.8

Allele description [Variation Report for NM_000363.5(TNNI3):c.5C>T (p.Ala2Val)]

NM_000363.5(TNNI3):c.5C>T (p.Ala2Val)

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.5C>T (p.Ala2Val)

HGVS:

NC_000019.10:g.55157585G>A
NG_007866.2:g.5148C>T
NG_032759.1:g.14138C>T
NM_000363.5:c.5C>TMANE SELECT
NP_000354.4:p.Ala2Val
LRG_432t1:c.5C>T
LRG_432:g.5148C>T
NC_000019.9:g.55668953G>A
NM_000363.4:c.5C>T
P19429:p.Ala2Val
c.5C>T

Protein change:

A2V

Links:

LOVD 3: TNNI3_000039; UniProtKB: P19429#VAR_043989; OMIM: 191044.0009; dbSNP: rs397516359

NCBI 1000 Genomes Browser:

rs397516359

Molecular consequence:

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

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
SCV000059961	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jun 28, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22940544, 19590045, 15070570, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059961

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jun 28, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I.

Henze M, Patrick SE, Hinken A, Scruggs SB, Goldspink P, de Tombe PP, Kobayashi M, Ping P, Kobayashi T, Solaro RJ.

Biochim Biophys Acta. 2013 Apr;1833(4):823-32. doi: 10.1016/j.bbamcr.2012.08.012. Epub 2012 Aug 25.

PubMed [citation]

PMID:: 22940544
PMCID:: PMC3548050

Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.

Carballo S, Robinson P, Otway R, Fatkin D, Jongbloed JD, de Jonge N, Blair E, van Tintelen JP, Redwood C, Watkins H.

Circ Res. 2009 Aug 14;105(4):375-82. doi: 10.1161/CIRCRESAHA.109.196055. Epub 2009 Jul 9.

PubMed [citation]

PMID:: 19590045

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059961.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Ala2Val variant in TNNI3 has been reported as homozygous in 2 individuals with DCM and segregated in the homozygous state in 1 affected sibling (Murphy 2004, LMM data). In vitro functional studies provide some evidence that the p.Ala2Val variant may impact protein function (Murphy 2004, Henze 2013). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has been identified in 0.03% (8/30592) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency raises the possibility that the variant does not cause disease in the heterozygous state but is not inconsistent with a recessive mode of inheritance. In summary, due to conflicting evidence, the clinical significance of the p.Ala2Val variant is uncertain. ACMG/AMP Criteria applied: PP1, PM3_Supporting, PS3_Supporing, BS1_Supporting, BP4.

#	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		4	not provided	1	not provided

Last Updated: May 7, 2024

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