rs397516460

Positions:

• chr1-201365247-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. 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 (★★). 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.355C>T	p.His119Tyr	missense_variant	10/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.355C>T	p.His119Tyr	missense_variant	10/17		NM_001276345.2	A2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2015

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2018

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;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516460; hg19: chr1-201334375;