1-201365281-C-G

Variant names:

• chr1-201365281-C-G
• rs397516459
• NM_001276345.2:c.321G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001276345.2(TNNT2):​c.321G>C​(p.Lys107Asn) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K107E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.37
• Publications: 0 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 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 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
• PP5: Variant 1-201365281-C-G is Pathogenic according to our data. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-201365281-C-G is described in CliVar as Pathogenic. Clinvar id is 2100789.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.321G>C	p.Lys107Asn	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.321G>C	p.Lys107Asn	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 97 of the TNNT2 protein (p.Lys97Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25524337; Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TNNT2 function (PMID: 28973951, 33025817). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;D;.;.;.;.;D;.;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;.;D;.;.;D;.
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.;.;.;.;.;.;.;.
PhyloP100		3.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D;D;.;.;.;.;.;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;.;.;D;.;.;.
Vest4		0.90
MutPred		0.63		.;.;.;Loss of ubiquitination at K107 (P = 0.0051);.;.;.;.;.;Loss of ubiquitination at K107 (P = 0.0051);.;.;
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.98
Mutation Taster		=0/100	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: rs397516459; hg19: chr1-201334409;