rs727503506

Variant names:

• chr19-55154743-C-G
• rs727503506
• NM_000363.5:c.370G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-55154743-C-G
• chr19-55154743-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000363.5(TNNI3):​c.370G>C​(p.Glu124Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. E124K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense, splice_region
• Scores: Splicing: ADA: 0.006259
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 7.79

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]

ENSG00000267110 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a chain Troponin I, cardiac muscle (size 208) in uniprot entity TNNI3_HUMAN there are 156 pathogenic changes around while only 18 benign (90%) in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 19-55154743-C-G is Pathogenic according to our data. Variant chr19-55154743-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165520.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.370G>C	p.Glu124Gln	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.370G>C	p.Glu124Gln	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_000363.5	ENSP00000341838.5
ENSG00000267110	ENST00000587871.1	n.*472G>C		downstream_gene_variant		5		ENSP00000473050.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249260 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33478

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44716

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53414

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111936

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:1 Uncertain:1

May 17, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with glutamine at codon 124 in the TNNT-binding region of the TNNI3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with hypertrophic cardiomyopathy (PMID: 25086479, 28498465, 28790153, 29875424, 30297972, 33495597, 32815737, 36166435; ClinVar SCV001156308.2, SCV000284657.9). This variant has been identified in 2/249260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy Pathogenic:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 124 of the TNNI3 protein (p.Glu124Gln). This variant is present in population databases (rs727503506, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25086479, 28498465, 28790153; internal data). ClinVar contains an entry for this variant (Variation ID: 165520). 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 tolerated. 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. -

not specified Uncertain:1

Oct 14, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu124Gln variant in TNNI3 has not been previously reported in individuals w ith cardiomyopathy. Glutamic acid (Glu) at position 124 is highly conserved in m ammals and across most evolutionarily distant species and the change to glutamin e (Gln) was predicted to be pathogenic using a computational tool clinically val idated by our laboratory. This tool's pathogenic prediction is estimated to be c orrect 94% of the time (Jordan 2011). Additional computational analyses (biochem ical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional info rmation is needed to fully assess the clinical significance of this variant. -

Hypertrophic cardiomyopathy 7 Uncertain:1

Apr 07, 2020

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The TNNI3 Glu124Gln has been previously identified in a Taiwanese HCM proband, that suffered a resuscitated cardiac arrest, the variant segregated to an affected sibling (Chiou KR, et al., 2015). It has also been identified in 4 HCM probands (1 Chinese, 1 Caucasian, 2 unknown ethnicity) by Genedx (personal communication) and 1 HCM proband of Asian descent by the Laboratory of Molecular Medicine (personal communication). The variant has been seen as a singleton event in the East Asian sub-population in the Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/). We identified this variant in HCM proband of Chinese descent. The proband has a family history of HCM, however segregation was not possible. Computational tools PolyPhen2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious, however SIFT predicts this variant to be "Tolerated". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) the variant is rare in the general population (PM2) and has been identified in at least 7 HCM probands (PS4_moderate), therefore we classify TNNI3 Glu124Gln as a variant of "uncertain significance" -

not provided Uncertain:1

Feb 04, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an adult Chinese male from an HCM cohort who also harbored a nonsense variant in the GLA gene (Zhao et al., 2017); Reported in an Australian proband from an HCM cohort, though patient-specific clinical data were not provided (Burns et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance and as a likely pathogenic variant, but additional evidence is not available (ClinVar Variant ID# 165520; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28498465, 25086479, 28790153) -

Cardiovascular phenotype Uncertain:1

Dec 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E124Q variant (also known as c.370G>C), located in coding exon 6 of the TNNI3 gene, results from a G to C substitution at nucleotide position 370. The glutamic acid at codon 124 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited and an additional alteration in a cardiac-related gene was identified in one case (Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:[ePub ahead of print]; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10:[ePub ahead of print]; Zhao Y et al. Int J Mol Med, 2017 Jul;40:121-129; Mazzarotto F et al. Genet Med, 2019 02;21:284-292). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
CardioboostCm	Uncertain	0.79
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.032	D;D
Polyphen		0.96	D;.
Vest4		0.83
MutPred		0.87		Gain of MoRF binding (P = 0.03);.;
MVP		0.96
MPC		0.71
ClinPred		0.64	D
GERP RS		4.4
Varity_R		0.73
Mutation Taster		=42/58	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0063
dbscSNV1_RF	Benign	0.084
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: rs727503506; hg19: chr19-55666111;