chr19-55154094-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM5 PP5_Very_Strong

The NM_000363.5(TNNI3):​c.485G>A​(p.Arg162Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,613,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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); 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).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 4.05
• Publications: 33 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: G2P, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: AR, AD Classification: STRONG 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000363.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-55154094-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 626844.
• PP5: Variant 19-55154094-C-T is Pathogenic according to our data. Variant chr19-55154094-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000363.5. You can select a different transcript below to see updated ACMG 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	NP_000354.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.485G>A	p.Arg162Gln	missense	Exon 7 of 8	ENSP00000341838.5	P19429
	TNNI3	ENST00000665070.1		c.518G>A	p.Arg173Gln	missense	Exon 7 of 8	ENSP00000499482.1	A0A590UJN1
	TNNI3	ENST00000714238.1		c.473G>A	p.Arg158Gln	missense	Exon 7 of 8	ENSP00000519518.1	A0AAQ5BHR0

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000402 AC: 10 AN: 249030 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461004 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 726832

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52744

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5630

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1112002

Other (OTH) AF: 0.0000663 AC: 4 AN: 60362

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152006 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74242

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

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000570 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
5	-	-	Hypertrophic cardiomyopathy 7 (5)
3	-	-	Hypertrophic cardiomyopathy (3)
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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Uncertain	0.15
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.062	T
MutationAssessor	Benign	0.83	L
PhyloP100		4.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.031	D
Sift4G	Benign	0.063	T
Polyphen		0.77	P
Vest4		0.75
MVP		0.91
MPC		0.85
ClinPred		0.16	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397516354; hg19: chr19-55665462; COSMIC: COSV52573571; COSMIC: COSV52573571;