rs45501500

Variant names:

• chr1-201363390-C-T
• rs45501500
• NM_001276345.2:c.506G>A
• TNNT2 p.Arg169Gln

Your query was ambiguous. Multiple possible variants found:

• chr1-201363390-C-T
• chr1-201363390-C-G

GermlineCancer (beta)

Variant summary

Our verdict is

Likely pathogenic

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 9 classification points (ACMG Germline Pathogenicity v2019): 9P and 0B. PS3PM1PM2PP5

The NM_001276345.2(TNNT2):c.506G>A (p.Arg169Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,876 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV000832104: Experimental studies have shown that this missense change affects TNNT2 function (PMID:20031601)." and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R169*: Uncertain_significance (ClinVar VariationId 43646, 2 stars); p.R169G: Uncertain_significance (ClinVar VariationId 2953222, 1 star); p.R169= (synonymous): Likely_benign (ClinVar VariationId 2951920, 1 star)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6
• Conservation: PhyloP100: 4.46
• Publications: 16 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 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• 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:):

Classification according to ACMG Germline Pathogenicity v2019

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

Our verdict: Likely_pathogenic. The variant received 9 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000832104: Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20031601).; SCV002768058: "Functional studies using porcine cardiac fibres demonstrated that this variant results in reduced calcium sensitivity (PMID: 20031601)."
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 4 pathogenic, 0 benign (OR vs. background: 45.0).
• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
• PP5: ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.506G>A	p.Arg169Gln	missense	Exon 12 of 17	NP_001263274.1	P45379-1
	TNNT2	NM_000364.4		c.506G>A	p.Arg169Gln	missense	Exon 12 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.506G>A	p.Arg169Gln	missense	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.506G>A	p.Arg169Gln	missense	Exon 12 of 17	ENSP00000499593.1	P45379-1
	TNNT2	ENST00000367322.6	TSL:1	c.473G>A	p.Arg158Gln	missense	Exon 11 of 15	ENSP00000356291.2	A0A499FJM7
	TNNT2	ENST00000367320.6	TSL:1	c.386G>A	p.Arg129Gln	missense	Exon 11 of 15	ENSP00000356289.2	P45379-12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Varity_R		0.088
gMVP		0.63
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45501500;

hg19: chr1-201332518;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar