rs730881069

chr19-55154172-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000363.5(TNNI3):c.407G>A(p.Arg136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 1.20

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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 chr19-55154172-C-G is described in Lovd as [Likely_pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-55154172-C-T is Pathogenic according to our data. Variant chr19-55154172-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181576.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=1}. Variant chr19-55154172-C-T is described in Lovd as [Pathogenic]. Variant chr19-55154172-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.407G>A	p.Arg136Gln	missense_variant	7/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.407G>A	p.Arg136Gln	missense_variant	7/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248592 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134966

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: 0.00000205 AC: 3 AN: 1460818 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726706

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	Reported as likely pathogenic by other clinical laboratories in ClinVar but additional evidence is not available (ClinVar Variant ID#181576; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23140321, 27532257, 20624503, 22765922, 24510615) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 08, 2019	- -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 14, 2023	This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 24510615, 24793961, 25132132, 27532257, 30297972, 35176171). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 20624503). This variant is present in 1/248592 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 181576). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20624503, 22765922, 24510615, 27532257, 28356264; Invitae). This variant is present in population databases (rs730881069, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the TNNI3 protein (p.Arg136Gln). -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 30, 2022

- -

Hypertrophic cardiomyopathy 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 24, 2020

The c.407G>A, p.Arg136Gln variant has 0.0004% allele frequency in the gnomAD database (1 out of 248,592 heterozygous alleles), indicating this is a rare allele. This sequence change has been observed in individuals affected with hypertrophic cardiomyopathy [PMID: 28356264; PMID:27532257; PMID: 24510615; PMID: 22765922; PMID: 20624503]. In silico tools(SIFT, PolyPhen-2, Align-GVGD, REVEL, and CADD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Based on available evidence this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2018

The p.R136Q variant (also known as c.407G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 407. The arginine at codon 136 is replaced by glutamine, an amino acid with highly similar properties, and is located in the TnC and actin binding domains. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (Millat G et al. Eur J Med Genet 2010 Jul;53:261-7; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Teirlinck CH et al. BMC Med. Genet., 2012 Nov;13:105; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is 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	Benign	0.19
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.45	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.86	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.60
Sift	Benign	0.094	T;.
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.63		Loss of methylation at R136 (P = 0.0197);.;
MVP		0.93
MPC		1.6
ClinPred		0.88	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.63		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730881069; hg19: chr19-55665540; COSMIC: COSV52572523; COSMIC: COSV52572523;