chr1-201364336-G-A

Variant names:

• chr1-201364336-G-A
• rs74315379
• NM_001276345.2:c.451C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.451C>T​(p.Arg151Trp) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003921976: 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).; SCV000209242: Affects cardiac muscle contractile dynamics by decreasing Ca2+ sensitivity of activation, reducing affinity of Ca2+ binding in the troponin complex, and/or increasing the rate of Ca2+ dissociation from the thin filament (Lu et al., 2003; Mirza et al., 2005; Venkatraman et al., 2005; Robinson et al., 2007; Liu et al., 2012; Sommese et al., 2013; Memo et al., 2013; Gollapudi et al., 2015); SCV000203869: "In vitro functional studies provide some evidence that the p.Arg141Trp variant may impact protein function (Lu 2003, Venkatraman 2003, Venkatraman 2005, Mirza 2005, Robinson 2007, Liu 2012, Memo 2013, Sommerse 2013)."; SCV000285650: Experimental studies have shown that this missense change affects TNNT2 function (PMID:14654368, 18349139, 18606313, 23539503, 24367593).; SCV001572362: Multiple publications report in-vitro or in-vivo experimental evidence that the variant results in calcium desensitization in cardiac muscle fibers (e.g. Lu_2003, Mirza_2005, Gollapudi_2015).; SCV005519978: "In multiple assays testing TNNT2 function, this variant showed functionally abnormal results" (Mirza M et al. J Biol Chem, 2005 Aug;280:28498-506; Robinson P et al. Circ Res, 2007 Dec;101:1266-73; Liu B et al. PLoS One, 2012 Jun;7:e38259; Gollapudi SK et al. Am J Physiol Heart Circ Physiol, 2015 Apr;308:H884-93).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 5.39
• Publications: 17 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003921976: 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).; SCV000209242: Affects cardiac muscle contractile dynamics by decreasing Ca2+ sensitivity of activation, reducing affinity of Ca2+ binding in the troponin complex, and/or increasing the rate of Ca2+ dissociation from the thin filament (Lu et al., 2003; Mirza et al., 2005; Venkatraman et al., 2005; Robinson et al., 2007; Liu et al., 2012; Sommese et al., 2013; Memo et al., 2013; Gollapudi et al., 2015); SCV000203869: "In vitro functional studies provide some evidence that the p.Arg141Trp variant may impact protein function (Lu 2003, Venkatraman 2003, Venkatraman 2005, Mirza 2005, Robinson 2007, Liu 2012, Memo 2013, Sommerse 2013)."; SCV000285650: Experimental studies have shown that this missense change affects TNNT2 function (PMID: 14654368, 18349139, 18606313, 23539503, 24367593).; SCV001572362: Multiple publications report in-vitro or in-vivo experimental evidence that the variant results in calcium desensitization in cardiac muscle fibers (e.g. Lu_2003, Mirza_2005, Gollapudi_2015).; SCV005519978: "In multiple assays testing TNNT2 function, this variant showed functionally abnormal results" (Mirza M et al. J Biol Chem, 2005 Aug;280:28498-506; Robinson P et al. Circ Res, 2007 Dec;101:1266-73; Liu B et al. PLoS One, 2012 Jun;7:e38259; Gollapudi SK et al. Am J Physiol Heart Circ Physiol, 2015 Apr;308:H884-93).
• PM1: In a hotspot region, there are 10 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 chr1-201364335-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181617.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 1-201364336-G-A is Pathogenic according to our data. Variant chr1-201364336-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12414.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.451C>T	p.Arg151Trp	missense	Exon 11 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.451C>T	p.Arg151Trp	missense	Exon 11 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.451C>T	p.Arg151Trp	missense	Exon 11 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.451C>T	p.Arg151Trp	missense	Exon 11 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.418C>T	p.Arg140Trp	missense	Exon 10 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.331C>T	p.Arg111Trp	missense	Exon 10 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460682 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726660

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111722

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Dilated cardiomyopathy 1D (5)
4	-	-	not provided (4)
2	-	-	Cardiomyopathy (2)
2	-	-	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (2)
2	-	-	Hypertrophic cardiomyopathy 2 (2)
1	-	-	Cardiomyopathy, familial restrictive, 3 (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial isolated dilated cardiomyopathy (1)
1	-	-	Primary dilated cardiomyopathy (1)
1	-	-	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.62		Loss of methylation at K156 (P = 0.1239)
MVP		0.94
MPC		1.5
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.76
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs74315379; hg19: chr1-201333464;