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 Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 17 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP5_Very_Strong

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) 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 ACMG Germline Pathogenicity v2019

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: Pathogenic. The variant received 17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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); SCV000280508: There is also expertimental evidence that suggests this variant dirupts protein-protein interactions.; SCV000059952: "In vitro functional studies using a mammalian two-hybrid system suggests that this variant may impact protein function by affecting the interaction with other binding partners (troponin T and troponin C;" PMID:15698845); SCV000253837: Experimental studies have shown that this missense change affects TNNI3 function (PMID: 15698845).; SCV004819051: "A functional study has shown that this variant disrupts interactions with troponin C and T (PMID: 15698845)."; SCV001358527: "A functional study has shown that this variant disrupts interactions with troponin C and T (PMID: 15698845)."; SCV000996359: A mammalian two-hybrid system has shown that this missense change decreases troponin T and troponin C interaction (Doolan A, et al., 2005), whereas crystal structure modelling suggests that the Arg162Gln affects troponin C stability (Ramachandran G, et al., 2013).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 10 pathogenic, 0 benign (OR vs. background: 105.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000655 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R162P: Pathogenic/Likely_pathogenic (ClinVar VariationId 43390, 2 stars); Other variants at the same amino acid residue (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)
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (29/29 total P/LP).

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

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