chr1-201363376-TCTC-T

Variant names:

• chr1-201363376-TCTC-T
• rs397516470
• NM_001276345.2:c.517_519delGAG

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PM1 PM2 PP5_Very_Strong BP3

The NM_001276345.2(TNNT2):​c.517_519delGAG​(p.Glu173del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000060251: Functional studies indicate that this variant may impact protein function (Tobacman 1999, Harada 2000, Manning 2012), though these in vitro assays may not accurately represent biological function." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E173E) has been classified as Likely benign. The gene TNNT2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.74
• Publications: 12 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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

Specifications for TNNT2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000060251: Functional studies indicate that this variant may impact protein function (Tobacman 1999, Harada 2000, Manning 2012), though these in vitro assays may not accurately represent biological function.; SCV004839106: "In-vivo functional studies using a transgenic mouse knock-in model have shown that this variant causes a phenotype consistent with hypertrophic cardiomyopathy, including sarcomeric abnormalities, cellular hypertrophy, decreased calcium uptake activity, and myofilament disarray (PMID: 23434821, 24480310, 26714042). Additional in-vitro functional studies using transfected porcine cardiac myofibrils have shown that this variant causes altered troponin affinity and increased calcium sensitivity (PMID: 10731693)."; SCV000541933: Experimental studies have shown that this variant affects TNNT2 function (PMID: 10731693, 22579624, 24480310, 27036851).; SCV000739945: "A combination of in vitro and in vivo studies showed disrupted weak electrostatic actomyosin binding in motility assays and severe cardiac remodeling and myofilament disarray in transgenic mice (Moore RK et al. Arch Biochem Biophys. 2014;552-553:21-8)."; SCV000209278: Published functional studies in E. coli demonstrated p.(E163del) (reported as deltaE160) resulted in recombinant troponin with increased calcium ion sensitivity (Messer et al., 2016); Published functional studies using transgenic mice demonstrated that the del160E (c.487_489delGAG) variant leads to cellular hypertrophy and myofilament disarray as well as impairments in contraction, relaxation, and calcium handling (Moore et al., 2013; Moore et al., 2014); SCV000924966: several functional studies have been done to investigate the functional effect of this single amino acid deletion. Harada et al. (2000) report that "the mutant troponin T showed a slightly reduced potency in replacing the endogenous troponin complex in myofibrils and did not affect the inhibitory action of troponin I but potentiated the neutralizing action of troponin C, suggesting that the deletion of a single amino acid, Glu-160, in the strong tropomyosin-binding region affects the tropomyosin binding affinity of the entire troponin T molecule and alters the interaction between troponin I and troponin C within ternary troponin complex in the thin filament. This mutation also increased the Ca(2+) sensitivity of the myofibrillar ATPase activity, as in the case of other mutations in troponin T with clinical phenotypes of poor prognosis similar to that of Glu160." PMID:10970864 Manning et al (2012) found that this variant results in a decrease in flexibility of the troponin T protein, which results in a tightening of the helix at the C-terminus of TNT1 that both stiffens TNT1 and pulls on the cTnT linker. This results in dramatically different physical behavior. Moore et al (2014) evaluated the in vivo effects of this variant in mutant mice. Severe, progressive cardiac remodeling and myofilament disarray were observed in vivo. In vitro motility assays were consistent with weaker electrostatic binding conditions and increased calcium sensitivity. Messer et al (2016) also replicated increased calcium sensitivity in vitro in troponin T protein harboring this variant.
• PM1: In a hotspot region, there are 4 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
• PP5: Variant 1-201363376-TCTC-T is Pathogenic according to our data. Variant chr1-201363376-TCTC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_001276345.2

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.517_519delGAG	p.Glu173del	conservative_inframe_deletion	Exon 12 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.517_519delGAG	p.Glu173del	conservative_inframe_deletion	Exon 12 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.517_519delGAG	p.Glu173del	conservative_inframe_deletion	Exon 12 of 16	NP_001393652.1	P45379-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.517_519delGAG	p.Glu173del	conservative_inframe_deletion	Exon 12 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.484_486delGAG	p.Glu162del	conservative_inframe_deletion	Exon 11 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.397_399delGAG	p.Glu133del	conservative_inframe_deletion	Exon 11 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
2	-	-	Hypertrophic cardiomyopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (1)
1	-	-	Hypertrophic cardiomyopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=44/56	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516470; hg19: chr1-201332504; COSMIC: COSV105863766; COSMIC: COSV105863766;