1-201361970-ATCT-A

Variant names:

• chr1-201361970-ATCT-A
• rs45578238
• NM_001276345.2:c.659_661delAGA

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.659_661delAGA​(p.Lys220del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000274 in 1,461,878 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: "SCV000840076: "In addition, experiential evidences has shown that the c.629_631delAGA (p.K210del) variant alters TNNT2 activity (PMID:11773635, 12186860, 12923187, 14654368, 15623536)."" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 5.06
• Publications: 44 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

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000840076: "In addition, experiential evidences has shown that the c.629_631delAGA (p.K210del) variant alters TNNT2 activity (PMID: 11773635, 12186860, 12923187, 14654368, 15623536)."; SCV002768092: Functional studies have suggested loss of function, gain of function and dominant negative mechanisms based on calcium sensitivity, contractibility and mouse models. PMID: 18612386, 32098556, 33025817; ClinGen.; SCV000060262: Multiple functional studies support a disease-causing role (Venkatraman 2003 PMID: 12923187, Venkatraman 2005 PMID: 15623536, Ahmad 2008 PMID: 18612386, Sfichi-Duke 2010 PMID: 20079745, Liu 2012 PMID: 22675533, Sugihara 2013 PMID: 23383212).; SCV004821976: Experimental functional studies using rabbit cardiac muscle fibers have shown that this variant causes a disruption to calcium sensitivity (PMID: 11773635, 12923187, 15623536, 15923195). Recombinant human troponin complexes expressing this variant have shown that this variant causes decreased filament mobility (PMID: 12186860, 15923195).; SCV000209279: Published functional studies demonstrate a damaging effect; c.629_631delAGA causes a decrease in maximum speed of heart muscle contraction, leading to impaired systolic function and cardiac dilation (Mogensen et al., 2004; Venkatraman et al., 2003); SCV000280531: The mutant protein has a reduced calcium sensitivity and requires higher free calcium concentrations for force generation and to activate ATPase (Morimoto et al. 2002, Robinson et al. 2002, Venkatraman et al. 2003).; SCV000320613: Functional in vitro analyses have reported this alteration to result in reduced cardiac contractile function (Morimoto S et al. PNAS. 2002;99(2):913-8; Venkatraman G et al. J Biol Chem. 2005;280(18):17584-92).; SCV000697567: Functional studies have shown an aberrant response and sensitivity to calcium ions compared to WT (Robinson_JBC_2002; Morimoto_PNAS_2002).; SCV000541926: Experimental studies have shown that this variant affects TNNT2 function (PMID: 11773635, 12186860, 12923187, 15623536, 15923195, 17932326, 20079745, 22675533, 23383212, 23539503, 23663841).; SCV006064412: Experimental functional studies using rabbit cardiac muscle fibers have shown that this variant causes a disruption to calcium sensitivity (PMID: 11773635, 12923187, 15623536, 15923195). Recombinant human troponin complexes expressing this variant have shown that this variant causes decreased filament mobility (PMID: 12186860, 15923195).; SCV005357294: Functional studies demonstrate this variant results in reduced calcium sensitivity (Morimoto et al. 2002. PubMed ID: 11773635; Venkatraman et al. 2003. PubMed ID: 12923187) and a decrease in maximum speed of heart muscle contraction (Venkatraman et al. 2003. PubMed ID: 12923187).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001276345.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-201361970-ATCT-A is Pathogenic according to our data. Variant chr1-201361970-ATCT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.659_661delAGA	p.Lys220del	disruptive_inframe_deletion	Exon 14 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.650_652delAGA	p.Lys217del	disruptive_inframe_deletion	Exon 13 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.650_652delAGA	p.Lys217del	disruptive_inframe_deletion	Exon 13 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.659_661delAGA	p.Lys220del	disruptive_inframe_deletion	Exon 14 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.617_619delAGA	p.Lys206del	disruptive_inframe_deletion	Exon 12 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.530_532delAGA	p.Lys177del	disruptive_inframe_deletion	Exon 12 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461878 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112002

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
7	-	-	Dilated cardiomyopathy 1D (7)
3	-	-	Primary dilated cardiomyopathy (3)
2	-	-	Cardiomyopathy (2)
2	-	-	Cardiovascular phenotype (2)
2	-	-	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (2)
1	-	-	Cardiomyopathy, familial restrictive, 3 (1)
1	-	-	Hypertrophic cardiomyopathy 2 (1)
1	-	-	TNNT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=6/94	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: rs45578238; hg19: chr1-201331098; COSMIC: COSV52663363; COSMIC: COSV52663363;