rs397516460

Variant names:

• chr1-201365247-G-A
• rs397516460
• NM_001276345.2:c.355C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM1 PM2 PP3_Moderate

The NM_001276345.2(TNNT2):​c.355C>T​(p.His119Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H119H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.98
• Publications: 4 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: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_001276345.2 (TNNT2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.355C>T	p.His119Tyr	missense_variant	Exon 10 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.355C>T	p.His119Tyr	missense_variant	Exon 10 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.His109Tyr variant in TNNT2 has not been previously reported in individuals with cardiomyo pathy or in large population studies; however, the c.324_325delinsGT variant pro ducing the same amino acid change (p.His109Tyr) has been identified by our labor atory in 1 Caucasian individual with adolescent-onset DCM. Histidine (His) at po sition 109 is highly conserved in mammals and across evolutionarily distant spec ies and the change to tyrosine (Tyr) was predicted to be pathogenic using a comp utational tool clinically validated by our laboratory. This tool's pathogenic pr ediction is estimated to be correct 94% of the time (Jordan 2011). In summary, w hile there is some suspicion for a pathogenic role, the clinical significance of the p.His109Tyr variant is uncertain. -

Cardiovascular phenotype Uncertain:1

Nov 29, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325C>T (p.H109Y) alteration is located in exon 9 (coding exon 8) of the TNNT2 gene. This alteration results from a C to T substitution at nucleotide position 325, causing the histidine (H) at amino acid position 109 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Uncertain	0.90
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;.;.;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.;.;.;.;.;.;.
PhyloP100		10
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D;D;.;.;.;.;.;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;D;D;D;D
Sift4G	Benign	0.077	T;T;T;D;D;T;D;T;.;D;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;D;.;.
Vest4		0.88
MutPred		0.48		.;.;.;Gain of phosphorylation at H119 (P = 0.0774);.;.;.;.;.;Gain of phosphorylation at H119 (P = 0.0774);.;
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.99
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397516460; hg19: chr1-201334375;