1-201365220-C-T

Variant names:

• chr1-201365220-C-T
• rs397516461
• NM_001276345.2:c.382G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001276345.2(TNNT2):​c.382G>A​(p.Glu128Lys) variant causes a missense change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.15

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]

ENSG00000286600 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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, 0.914
• PP5: Variant 1-201365220-C-T is Pathogenic according to our data. Variant chr1-201365220-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43634.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.382G>A	p.Glu128Lys	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.382G>A	p.Glu128Lys	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Jan 14, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu118Lys variant in TNNT2 has not been reported in the literature, but has been identified by our laboratory in 1 infant with congenital DCM and was not id entified in either parent, thus likely occurring de novo. This variant has also not been identified in large and broad European American and African American po pulations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S), which increases the likelihood that the variant is pathogenic. However, we c annot exclude that it may be common in other populations. Glutamic acid (Glu) at position 118 is highly conserved in mammals and across evolutionarily distant s pecies, though dolphin has another amino acid at this position. The change to Ly sine (Lys) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to b e correct 94% of the time (Jordan 2011). In summary, the de novo occurrence and computational predictions support that this variant is likely pathogenic, though additional studies are needed to fully assess its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostCm	Uncertain	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;.;.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;D;.;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.5	D;D;.;.;N;.;.;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;.;.;D;.;.;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;T;D;T;D;.;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;D;.
Vest4		0.64
MutPred		0.73		.;.;.;Gain of ubiquitination at E128 (P = 0.0077);.;.;.;.;.;Gain of ubiquitination at E128 (P = 0.0077);
MVP		0.99
MPC		0.97
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.49
gMVP		0.94

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: rs397516461; hg19: chr1-201334348;