19-55151881-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_000363.5(TNNI3):c.586G>A(p.Asp196Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D196G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.32

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 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000363.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-55151881-C-G is described in Lovd as [Pathogenic].
• PP5: Variant 19-55151881-C-T is Pathogenic according to our data. Variant chr19-55151881-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55151881-C-T is described in Lovd as [Pathogenic]. Variant chr19-55151881-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5	c.586G>A	p.Asp196Asn	missense_variant	8/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.586G>A	p.Asp196Asn	missense_variant	8/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249562 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727214

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 7 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 29, 2002	- -
Likely pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 26, 2019	The c.586G>A (p.Asp196Asn) variant in the TNNI3 gene has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 11815426, 12707239, 15607392, 24111713, 25524337). This variant is observed at an ultra-low frequency in the general population (gnomAD database 2/280974) and is reported to be damaging by multiple bioinformatics algorithms. For these reasons, this variant has been classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	ClinVar contains an entry for this variant (Variation ID: 12422). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11815426, 12707239, 15607392, 24111713, 25524337, 26914223, 27532257). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894727, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 196 of the TNNI3 protein (p.Asp196Asn). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2021	The p.Asp196Asn variant in TNNI3 has been reported in at least 12 individuals with HCM and segregated with disease in 3 affected individuals from 2 families (Niimura 2002 PMID:11815426, Richard 2003 PMID:12707239, Mogensen 2004 PMID:15607392, Coppini 2014 PMID: 25524337, Berge 2014 PMID:24111713, Murphy 2016 PMID:26914223, Walsh 2017 PMID:27532257, Norrish 2019 PMID:31006259, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 12422) and has been identified in 0.002% (2/128706) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4_Strong, PP1, PM2_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This missense variant is located in the C-terminal mobile domain of the TNNI3 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 24111713, 25524337, 26914223, 27532257). In two unrelated families, this variant was found in 4 of 7 affected family members (PMID: 15607392). This variant has been reported in 3/277204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different nucleotide substitution (c.586G > C) resulting in the same amino acid change has been reported in an individual affected with recessive restrictive cardiomyopathy (PMID: 30953456). Based on available evidence, this variant is classified as Likely Pathogenic. -

Cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2023	This missense variant replaces aspartic acid with asparagine at codon 196 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 24111713, 25524337, 26914223, 27532257), and in an individual with a family history of hypertrophic cardiomyopathy (PMID: 34363016). In two unrelated families, this variant was identified in 4 of 7 family members affected with hypertrophic cardiomyopathy (PMID: 15607392). This variant has been identified in 2/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 01, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TNNI3: PM1, PM5, PP1, PS4:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	Mogensen et al. (2004) reported the D196N variant to be present in four affected individuals from two families with HCM; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20035081, 26526134, 23299917, 25637381, 11815426, 12707239, 25524337, 24111713, 15607392, 26914223, 27532257, 28971120, 21777381, 26440512, 26199943, 31006259) -

Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2022

The p.D196N variant (also known as c.586G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 586. The aspartic acid at codon 196 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in multiple individuals with hypertrophic cardiomyopathy (HCM) (Niimura H et al. Circulation, 2002 Jan;105:446-51; Richard P et al. Circulation, 2003 May;107:2227-32; Mogensen J et al. J. Am. Coll. Cardiol., 2004 Dec;44:2315-25; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;.
Vest4		0.41
MVP		0.99
MPC		1.7
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894727; hg19: chr19-55663249;