rs121964856

Variant names:

• chr1-201365297-C-A
• rs121964856
• NM_001276345.2:c.305G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201365297-C-A
• chr1-201365297-C-G
• chr1-201365297-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001276345.2(TNNT2):​c.305G>T​(p.Arg102Leu) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.06
• Publications: 137 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 20 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201365298-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 43627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 1-201365297-C-A is Pathogenic according to our data. Variant chr1-201365297-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 235063.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.305G>T	p.Arg102Leu	missense	Exon 10 of 17	NP_001263274.1
	TNNT2	NM_000364.4		c.305G>T	p.Arg102Leu	missense	Exon 10 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.305G>T	p.Arg102Leu	missense	Exon 10 of 16	NP_001393652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.305G>T	p.Arg102Leu	missense	Exon 10 of 17	ENSP00000499593.1
	TNNT2	ENST00000367322.6	TSL:1	c.272G>T	p.Arg91Leu	missense	Exon 9 of 15	ENSP00000356291.2
	TNNT2	ENST00000367320.6	TSL:1	c.291+313G>T		intron	N/A	ENSP00000356289.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Jan 18, 2012

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TNNT2 Arg92Leu (R92L; at the nucleotide level) The variant has been reported in at least 3 unrelated cases of HCM with moderate segregation data in one family and strong functional data available both in vitro and in a transgenic mouse model. Varnava et al. (2001) detected Arg92Leu in one case of HCM. Some papers appear to list this variant as “Arg102Leu”: Forissier et al. (1996) first reported “Arg102Leu” in a French family, where it segregated with disease in 4 family members (two affected sisters, who each had an affected child). Richard et al. (2003) found it in one HCM patient recruited in France Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Trp, which we categorize as very likely disease causing, and p.Arg92Gln, which we categorize as very likely disease causing. Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Glu83Lys, Val85Leu, Asp86Ala, Arg94Leu, Arg94Cys, and Lys97Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). In vitro functional data from Palm et al. (2001) suggests that a change at codon 92—whether Arg92Trp, Arg92Gln or Arg92Leu—impairs binding of troponin T to tropomyosin and makes the protein less effective at promoting the binding of tropomyosin to actin. Harada & Potter (2004) showed the variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. Haim et al. (2007) showed altered calcium handling in isolated myocytes from transgenic Arg94Leu mice. He et al. (2007) showed that transgenic mice bearing the Arg92Trp or Arg92Leu mutation had a greater “energy cost” for cardiac muscle contraction than wild-type mice. The magnitude of these changes was mutation-specific: Arg92Trp hearts showed more severe energetic abnormalities and greater contractile dysfunction than Arg92Leu hearts. Guinto et al. (2009) showed diastolic dysfunction in transgenic mice carrying the variant, and altered calcium kinetics in isolated transgenic myocytes. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Leucine. The Arginine at codon 92 is highly conserved across 39 vertebrate species examined (it is a Lysine in medaka) and surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In total the variant has not been seen in ~5540 published controls and publicly available population datsets. There is no variation at codon 92 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Forissier et al. (1996) did not find it in 50 controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Richard et al. (2003) did not find the variant in 100 (European?) controls.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.42		Loss of methylation at K103 (P = 0.0384)
MVP		0.94
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.67
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121964856; hg19: chr1-201334425; COSMIC: COSV99372082; COSMIC: COSV99372082;