1-201365636-G-T

Variant names:

• chr1-201365636-G-T
• rs397516451
• NM_001276345.2:c.268C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001276345.2(TNNT2):​c.268C>A​(p.Pro90Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 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. P90S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6
• Conservation: PhyloP100: 9.88
• Publications: 8 publications found

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

TNNT2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000286600 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201365635-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 181641.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.268C>A	p.Pro90Thr	missense	Exon 9 of 17	NP_001263274.1
	TNNT2	NM_000364.4		c.268C>A	p.Pro90Thr	missense	Exon 9 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.268C>A	p.Pro90Thr	missense	Exon 9 of 16	NP_001393652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.268C>A	p.Pro90Thr	missense	Exon 9 of 17	ENSP00000499593.1
	TNNT2	ENST00000367322.6	TSL:1	c.235C>A	p.Pro79Thr	missense	Exon 8 of 15	ENSP00000356291.2
	TNNT2	ENST00000367320.6	TSL:1	c.265C>A	p.Pro89Thr	missense	Exon 9 of 15	ENSP00000356289.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2 Pathogenic:1

Mar 17, 2025

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 9 of the TNNT2 gene that results in the amino acid substitution of Threonine for Proline at codon 90 was detected. The observed variant c.268C>A has a minor allele frequency of 0.00007% in the gnomAD database. The in silico prediction of the variant is damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a likely pathogenic.

Hypertrophic cardiomyopathy 4 Pathogenic:1

Jun 02, 2023

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant TNNT2:c.238C>A, p.(Pro80Thr), which is located in the coding exon 8 of the TNNT2 gene, results from a cytosine to adenine substitution at nucleotide position 238. The proline residue at protein position 80 is replaced by a Threonine. The affected protein region has been postulated as a hotspot region for Pathogenic and Likely Pathogenic variants associated with hypertrophic cardiomyopathy (PMID: 30696458). The variant colocalises with other Pathogenic variants [p.(Pro80Ser; ClinVarID: 43620 and p.(Pro80Leu); ClinVarID: 181641)] that have been described in ClinVar. In silico tools predict a deleterious effect on the protein structure and function (REVEL = 0.81). The variant is very rare in the overall population (no carriers in gnomAD, v4.1.0). In summary, the variant is classified as Likely pathogenic.

Dilated cardiomyopathy 1D Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Uncertain:1

Jan 12, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Feb 20, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The P80T variant of uncertain significance in the TNNT2 gene has not been published as pathogenic or benign to our knowledge. P80T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species, and in silico analysis predicts P80T is probably damaging to the protein structure/function. Furthermore, P80T is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant has also been identified in individuals referred for HCM genetic testing at GeneDx; however, segregation studies have been uninformative thus far. Moreover, while a variant in the same residue (P80S) has been reported to segregate with disease in a family with HCM and LVNC, the proband was also found to harbor a second variant in TNNT2 that likely contributed to his phenotype (Otsuka H et al., 2012). Thus, P80T lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.

Cardiomyopathy, familial restrictive, 3 Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy 2 Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Uncertain:1

Oct 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 181611). This missense change has been observed in individual(s) with clinical features of TNNT2-related conditions (PMID: 31737537). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 80 of the TNNT2 protein (p.Pro80Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.22		Gain of phosphorylation at P90 (P = 0.0194)
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.29
gMVP		0.95
Mutation Taster		=19/81	disease causing

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: rs397516451; hg19: chr1-201334764;