NM_000363.5:c.511G>A

Variant names:

• chr19-55154068-C-T
• rs121917761
• NM_000363.5:c.511G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000363.5(TNNI3):​c.511G>A​(p.Ala171Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A171V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 4.81
• Publications: 23 publications found

Genes affected

TNNI3 (HGNC:11947): (troponin I3, cardiac type) Troponin I (TnI), along with troponin T (TnT) and troponin C (TnC), is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle. TnI is the inhibitory subunit; blocking actin-myosin interactions and thereby mediating striated muscle relaxation. The TnI subfamily contains three genes: TnI-skeletal-fast-twitch, TnI-skeletal-slow-twitch, and TnI-cardiac. This gene encodes the TnI-cardiac protein and is exclusively expressed in cardiac muscle tissues. Mutations in this gene cause familial hypertrophic cardiomyopathy type 7 (CMH7) and familial restrictive cardiomyopathy (RCM). Troponin I is useful in making a diagnosis of heart failure, and of ischemic heart disease. An elevated level of troponin is also now used as indicator of acute myocardial injury in patients hospitalized with moderate/severe Coronavirus Disease 2019 (COVID-19). Such elevation has also been associated with higher risk of mortality in cardiovascular disease patients hospitalized due to COVID-19. [provided by RefSeq, Aug 2020]

TNNI3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• cardiomyopathy, familial restrictive, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1FF

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 19-55154068-C-T is Pathogenic according to our data. Variant chr19-55154068-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12429.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.511G>A	p.Ala171Thr	missense_variant	Exon 7 of 8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.511G>A	p.Ala171Thr	missense_variant	Exon 7 of 8	1	NM_000363.5	ENSP00000341838.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460592 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5308

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000446 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy, familial restrictive, 1 Pathogenic:1

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hypertrophic cardiomyopathy Pathogenic:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the TNNI3 protein (p.Ala171Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with restrictive cardiomyopathy or hypertrophic cardiomyopathy (PMID: 12531876, 27532257, 30384889, 35208637, 35838873; Internal data). ClinVar contains an entry for this variant (Variation ID: 12429). 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 disruptive. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 15961398, 16288990, 18423659). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Dec 28, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNNI3 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248984 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.511G>A has been reported in the literature in an individual affected with Restrictive Cardiomyopathy who was an only child and no clinical data or DNA was available on his deceased parents (example, Mogensen_2003). None of his children were identified as carriers of this variant. It has also been reported with a likely pathogenic classification in an individual reportedly affected with hypertrophic cardiomyopathy (HCM) within the Oxford Medical Genetics Laboratories (OMGL) testing cohort (example, Walsh_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Restrcitve/Hypertrophic Cardiomyopathy. At-least two publications report experimental evidence evaluating an impact on protein function (example, Gomes_2005, Yumoto_2005), however, none of these studies allows convincing conclusions about the variant effect. Briefly summarized, this variant demonstrated an increase in Calcium sensitivity of force development compared with WT cTnI, caused a decrease in ability of cTnI to inhibit actomyosin ATPase activity and using mixtures of WT and mutant cTnI, this variant was classified into the dominant group (along with two other variants) in actomyosin ATPase assays in the absence of calcium ion. Most of the mutants were able to activate actomyosin ATPase similarly to wild-type. As represented, the data on this variant do not allow unequivocal contributions to ascertain as a strong evidence surrounding the pathophysiology of disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A171T variant (also known as c.511G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 511. The alanine at codon 171 is replaced by threonine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy and restrictive cardiomyopathy (Mogensen J et al. J Clin Invest, 2003 Jan;111:209-16; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Janin A et al. Mol Diagn Ther, 2022 Sep;26:551-560; Preveden A et al. Medicina (Kaunas), 2022 Feb;58:[ePub ahead of print]). In an assay testing TNNI3 function, this variant showed a functionally abnormal result (Gomes AV et al. J Biol Chem, 2005 Sep;280:30909-15; Davis J et al. J Mol Cell Cardiol, 2008 May;44:891-904). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		4.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.80
Sift	Benign	0.042	D;.
Sift4G	Benign	0.11	T;T
Polyphen		0.99	D;.
Vest4		0.69
MutPred		0.84		Loss of helix (P = 0.0376);.;
MVP		0.96
MPC		1.7
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121917761; hg19: chr19-55665436;