TNNI3 p.Arg162Leu

Variant names:

• chr19-55154094-C-A
• rs397516354
• NM_000363.5:c.485G>T
• TNNI3 p.Arg162Leu

Your query was ambiguous. Multiple possible variants found:

• chr19-55154094-C-A
• chr19-55154093-CC-AA
• chr19-55154093-CC-GA
• chr19-55154093-CC-TA
• chr19-55154094-CG-AA
• chr19-55154093-CCG-TAA

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP5

The NM_000363.5(TNNI3):c.485G>T (p.Arg162Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). 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)

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.05
• Publications: 36 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: Likely_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	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 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

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>T p.Arg162Leu	missense	Exon 7 of 8	Prot: NP_000354.4

TNNI3 NM_000363.5

MANE Select

HGVSc / HGVSpc.485G>Tp.Arg162Leu

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>T p.Arg162Leu	missense	Exon 7 of 8	Prot: ENSP00000341838.5 UniProt:
	TNNI3 ENST00000665070.1		c.518G>T p.Arg173Leu	missense	Exon 7 of 8	Prot: ENSP00000499482.1 UniProt:
	TNNI3 ENST00000714238.1		c.473G>T p.Arg158Leu	missense	Exon 7 of 8	Prot: ENSP00000519518.1 UniProt:

TNNI3 ENST00000344887.10

TSL:1MANE Select

HGVSc / HGVSpc.485G>Tp.Arg162Leu

Exon rankExon 7 of 8

missense

Prot: ENSP00000341838.5UniProt: P19429

TNNI3 ENST00000665070.1

HGVSc / HGVSpc.518G>Tp.Arg173Leu

Exon rankExon 7 of 8

missense

Prot: ENSP00000499482.1UniProt: A0A590UJN1

TNNI3 ENST00000714238.1

HGVSc / HGVSpc.473G>Tp.Arg158Leu

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
CardioboostCm	Uncertain	0.20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	0.099
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.026	D
Mutation Taster	N/A	15/85	disease causing (ClinVar)
MutationAssessor	Benign	1.4	L
PhyloP100	Uncertain	4.0
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.9	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.80
VESM-3B	Benign	-11

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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar