rs727504243

Positions:

• chr19-55151857-G-A
• chr19-55151857-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000363.5(TNNI3):​c.610C>T​(p.Arg204Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,170 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204H) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a chain Troponin I, cardiac muscle (size 208) in uniprot entity TNNI3_HUMAN there are 86 pathogenic changes around while only 10 benign (90%) in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-55151856-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 19-55151857-G-A is Pathogenic according to our data. Variant chr19-55151857-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55151857-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.610C>T	p.Arg204Cys	missense_variant	8/8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.610C>T	p.Arg204Cys	missense_variant	8/8	1	NM_000363.5	ENSP00000341838.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2020	Reported in association with HCM in the published literature (Van Driest et al., 2003; Gomes et al., 2004; Walsh et al., 2017); Published functional studies demonstrate increased calcium sensitivity compared to wild type (Nguyen et al., 2016); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12860912, 26199943, 27532257, 27895589, 15524171, 30165862) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg204Cys (c.610 C>T) in the TNNI3 gene. This variant has been reported online in one case of HCM (http://cardiogenomics.med.harvard.edu). It has also been seen by another genetic testing laboratory, in two individuals with a clinical diagnosis of restrictive cardiomyopathy (verbal report). None of these cases have been reported in the literature (though reviews and compendiums do refer to this variant). Another variant at the same codon has been reported in association with both HCM and RCM (p.Arg204His, Kimura et al 1997, Koga et al 1996, Doolan et al 2005). In addition, multiple variants have been reported at nearby codons (p.Glu202Gly, p.Gly203Arg, p.Gly203Ser, p.Lys205Gln, see Willot et al 2010 review). The Arginine at codon 204 is completely conserved across species as are the neighboring amino acids. In silico analysis (PolyPhen2) predicts the variant to be probably damaging. The testing lab noted that the variant was absent in 100 Caucasian individuals and 100 African-American individuals. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Missense variants functionally proven to cause a loss of function effect by decreasing calcium sensitivity cause dilated cardiomyopathy (DCM). Missense variants functionally proven to cause a gain of function effect by increasing calcium sensitivity cause hypertrophic cardiomyopathy (HCM) (PMID: 21533915). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Only a single family has been reported with a recessive form of inheritance (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 15607392). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative missense change at the same residue (p.Arg204Cys) has been reported as pathogenic, and observed in patients with restrictive cardiomyopathy (RCM) and HCM (ClinVar, PMID: 27895589). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and reported in multiple patients with HCM, RCM and infantile ventricular septal defects (ClinVar, PMID: 27895589, PMID: 31912959, PMID: 20569525). Some of these reports were de novo. (P) 1002 - Moderate functional evidence supporting abnormal protein function. Analysis of animal model muscle fibres found this variant results in increased calcium sensitivity and reduced interactions with Troponins C and T (PMID: 27895589). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 16, 2023

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. This variant disrupts the p.Arg204 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15698845, 18801787, 20569525, 29176140). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 27895589). 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. ClinVar contains an entry for this variant (Variation ID: 177631). This missense change has been observed in individuals with dilated cardiomyopathy, restrictive cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27532257, 33906374, 34036930). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the TNNI3 protein (p.Arg204Cys). -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 03, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg204Cys variant in TNNI3 has been identified by our laboratory in 1 child with features of RCM and HCM and 1 child with RCM and Vfib. The variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg204Cys variant may impact protein function (Cui 2013 [conference abstract]) . However, these types of assays may not accurately represent biological functio n. Additionally, a different amino acid alteration at this position (p.Arg204His ) is likely pathogenic and has also been identified in individuals with RCM and/ or HCM, supporting that a change at this position may not be tolerated. In summa ry, while there is some suspicion for a pathogenic role, the clinical significan ce of the p.Arg204Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.87		Loss of MoRF binding (P = 0.0051);.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504243; hg19: chr19-55663225; COSMIC: COSV52571349; COSMIC: COSV52571349;