chr1-201359253-G-T

Position:

• chr1-201359253-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001276345.2(TNNT2):​c.854C>A​(p.Ser285Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.898

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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, 10 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.854C>A	p.Ser285Tyr	missense_variant, splice_region_variant	17/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.854C>A	p.Ser285Tyr	missense_variant, splice_region_variant	17/17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 09, 2020

The p.Ser275Tyr variant in TNNT2 has been identified by our laboratory in one individual with infant onset LV dysfunction and segregated with disease in two siblings with infant onset DCM. The variant was identified in an unaffected parent in this family. Another variant at the same position, p.Ser275Phe has been reported in a Portuguese patient with DCM (Sousa 2019 PMID: 30871747). The p.Ser275Tyr variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ser275Tyr variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3. -

TNNT2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The TNNT2 c.824C>A variant is predicted to result in the amino acid substitution p.Ser275Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
CardioboostCm	Benign	0.032
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	.;.;.;.;D;.;.;.;.;.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.1	.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;D;.;.;.;.;.;.;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;D;.;.;.;.;.;.;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.99	.;.;.;.;D;.;.;.;.;.;.
Vest4		0.31
MutPred		0.30		.;.;.;.;Loss of disorder (P = 0.0377);.;.;.;.;.;.;
MVP		0.96
MPC		1.5
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.59
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs876658029; hg19: chr1-201328381;