NM_000363.5:c.485G>A

Variant names:

• chr19-55154094-C-T
• rs397516354
• NM_000363.5:c.485G>A
• TNNI3 p.Arg162Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO7_SupportingO8_Supporting

The NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000322 (AC=47) in the gnomAD database across 1,461,004 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000209175: Published in vitro functional studies using HEK293 cells showed that the R162Q variant results in a 50% reduction of the troponin I and troponin C interaction (Doolan et al., 2005)" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R162P: Pathogenic/Likely_pathogenic (ClinVar VariationId 43390, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R162?: Uncertain_significance (ClinVar VariationId 454407, 1 star); p.R162G: Uncertain_significance (ClinVar VariationId 3071848, 1 star); p.R162= (synonymous): Likely_benign (ClinVar VariationId 3231263, 2 stars); p.R162= (synonymous): Likely_benign (ClinVar VariationId 1060070, 1 star); p.R162W: Uncertain_significance (ClinVar VariationId 161396, 3 stars) The variant has been observed in cBioPortal in 3 samples across 3 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:29
• Conservation: PhyloP100: 4.05
• Publications: 20 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
• hypertrophic cardiomyopathy 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• cardiomyopathy, familial restrictive, 1

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

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for TNNI3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000066 — very rare (O3 supporting [+1])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 10 pathogenic, 0 benign (OR vs. background: 105.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.81 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000363.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TNNI3 NM_000363.5	MANE Select	c.485G>A p.Arg162Gln	missense	Exon 7 of 8	Prot: NP_000354.4

TNNI3 NM_000363.5

MANE Select

HGVSc / HGVSpc.485G>Ap.Arg162Gln

Exon rankExon 7 of 8

missense

Prot: NP_000354.4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TNNI3 ENST00000344887.10	TSL:1MANE Select	c.485G>A p.Arg162Gln	missense	Exon 7 of 8	Prot: ENSP00000341838.5 UniProt:
	TNNI3 ENST00000665070.1		c.518G>A p.Arg173Gln	missense	Exon 7 of 8	Prot: ENSP00000499482.1 UniProt:
	TNNI3 ENST00000714238.1		c.473G>A p.Arg158Gln	missense	Exon 7 of 8	Prot: ENSP00000519518.1 UniProt:

TNNI3 ENST00000344887.10

TSL:1MANE Select

HGVSc / HGVSpc.485G>Ap.Arg162Gln

Exon rankExon 7 of 8

missense

Prot: ENSP00000341838.5UniProt: P19429

TNNI3 ENST00000665070.1

HGVSc / HGVSpc.518G>Ap.Arg173Gln

Exon rankExon 7 of 8

missense

Prot: ENSP00000499482.1UniProt: A0A590UJN1

TNNI3 ENST00000714238.1

HGVSc / HGVSpc.473G>Ap.Arg158Gln

Exon rankExon 7 of 8

missense

Prot: ENSP00000519518.1UniProt: A0AAQ5BHR0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:152006	Cov:31
GnomAD2 exomes	AF: 0.0000402	AC:10	Hom:	AN:249030	Cov:
GnomAD4 exome	AF: 0.0000322	AC:47	Hom:0	AN:1461004	Cov:32
GnomAD4 genome Warning	AF: 0.00000658	AC:1	Hom:0	AN:152006	Cov:31
TOPMed (Bravo)	AF: 0.0000113	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000552	AC:5	Hom:0	AN:90516	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122136	Cov:
Turkish Variome	AF: 0.000647	AC:1	Hom:0	AN:1546	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000449	3	66888
SCHEMA(Schizophrenia)	0.0000291	3	103196	0.0000271	5	184284

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
6	-	-	Hypertrophic cardiomyopathy 7 (6)
4	-	-	Hypertrophic cardiomyopathy (4)
2	-	-	Cardiomyopathy (2)
2	-	-	Cardiovascular phenotype (2)
2	-	-	Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF (2)
2	-	-	Primary familial hypertrophic cardiomyopathy (2)
1	-	-	Dilated cardiomyopathy 1FF (1)
1	-	-	TNNI3-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
CardioboostCm	Uncertain	0.15
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.61	D
FuncVEP CTI	Benign	0.38
GPN-Star LLR	N/A	-6.4
GPN-Star score	N/A	6.4
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.062	T
Mutation Taster	N/A	14/86	disease causing (ClinVar)
MutationAssessor	Benign	0.83	L
PhyloP100	Uncertain	4.0
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.36
Sift	Benign	0.031	D
Sift4G	Benign	0.063	T
Varity_R	N/A	0.33
VESM-3B	Benign	-7.1

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs397516354;

hg19: chr19-55665462;

COSMIC: COSV52573571;

COSMIC: COSV52573571;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar