NM_000363.5(TNNI3):c.347C>G (p.Ala116Gly) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 19, 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:: RCV000698206.7

Allele description [Variation Report for NM_000363.5(TNNI3):c.347C>G (p.Ala116Gly)]

NM_000363.5(TNNI3):c.347C>G (p.Ala116Gly)

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.347C>G (p.Ala116Gly)

HGVS:

NC_000019.10:g.55154766G>C
NG_007866.2:g.7967C>G
NM_000363.5:c.347C>GMANE SELECT
NP_000354.4:p.Ala116Gly
LRG_432t1:c.347C>G
LRG_432:g.7967C>G
NC_000019.9:g.55666134G>C
NM_000363.4:c.347C>G

Protein change:

A116G

Links:

dbSNP: rs777177571

NCBI 1000 Genomes Browser:

rs777177571

Molecular consequence:

NM_000363.5:c.347C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000826856	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21846512, 25685665, 28492532
SCV004819068	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21846512, 25685665, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000826856

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 19, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004819068

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 27, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy.

Millat G, Bouvagnet P, Chevalier P, Sebbag L, Dulac A, Dauphin C, Jouk PS, Delrue MA, Thambo JB, Le Metayer P, Seronde MF, Faivre L, Eicher JC, Rousson R.

Eur J Med Genet. 2011 Nov-Dec;54(6):e570-5. doi: 10.1016/j.ejmg.2011.07.005. Epub 2011 Aug 4.

PubMed [citation]

PMID:: 21846512

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000826856.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 116 of the TNNI3 protein (p.Ala116Gly). This variant is present in population databases (rs777177571, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 21846512). ClinVar contains an entry for this variant (Variation ID: 575867). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 25685665). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 All of Us Research Program, National Institutes of Health, SCV004819068.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces alanine with glycine at codon 116 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study using recombinant mouse protein has shown that this variant causes conformational changes but no alteration to binding affinity to TnT (PMID: 25685665). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 21846512). This variant has been identified in 5/280832 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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