chr1-201365261-G-T

Variant names:

• chr1-201365261-G-T
• NM_001276345.2:c.341C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_001276345.2(TNNT2):​c.341C>A​(p.Ala114Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A114V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.98

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]

ENSG00000286600 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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, 14 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 chr1-201365261-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177633.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=8, Pathogenic=1}.
• PP5: Variant 1-201365261-G-T is Pathogenic according to our data. Variant chr1-201365261-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1403198.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.341C>A	p.Ala114Glu	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.341C>A	p.Ala114Glu	missense_variant	Exon 10 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Ala104 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9140840, 23396983, 27532257, 28790153). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. ClinVar contains an entry for this variant (Variation ID: 1403198). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28771489; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 104 of the TNNT2 protein (p.Ala104Glu). -

Cardiovascular phenotype Uncertain:1

May 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A104E variant (also known as c.311C>A), located in coding exon 8 of the TNNT2 gene, results from a C to A substitution at nucleotide position 311. The alanine at codon 104 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant was detected in a hypertrophic cardiomyopathy (HCM) case; however, clinical details were limited, and an additional cardiac variant was also reported (Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465). Another alteration at the same codon, p.A104V (c.311C>T), has been described in HCM cohorts; however, in several cases, clinical detail or gene analysis was limited or the variant co-occurred with pathogenic mutations in other cardiomyopathy-associated genes (Nakajima-Taniguchi C et al. J. Mol. Cell. Cardiol. 1997 Feb;29(2):839-43; Lopes LR et al. Heart, 2015 Feb;101:294-301; Ingles J et al. Circ Cardiovasc Genet. 2017 Apr;10(2); Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
CardioboostCm	Uncertain	0.10
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;.;.;D;.;.;.;.;D;.;.
Eigen	Benign	0.070
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.14	.;.;.;N;.;.;.;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N;N;.;.;.;.;N;N;N;N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;D;.;.;.;.;T;D;D;D;D
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.75, 0.88	.;.;.;P;.;.;.;.;P;.;.
Vest4		0.37
MutPred		0.63		.;.;.;Loss of MoRF binding (P = 0.4017);.;.;.;.;.;Loss of MoRF binding (P = 0.4017);.;
MVP		0.95
MPC		1.1
ClinPred		0.88	D
GERP RS		4.1
Varity_R		0.25
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-201334389;