rs397516471

Variant names:

• chr1-201363348-C-A
• rs397516471
• NM_001276345.2:c.548G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201363348-C-A
• chr1-201363348-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_001276345.2(TNNT2):​c.548G>T​(p.Arg183Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.98
• Publications: 15 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 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 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 chr1-201363349-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165542.
• PP5: Variant 1-201363348-C-A is Pathogenic according to our data. Variant chr1-201363348-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 691967.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.548G>T	p.Arg183Leu	missense_variant	Exon 12 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.548G>T	p.Arg183Leu	missense_variant	Exon 12 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1D Pathogenic:1

Jul 18, 2019

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.518G>T (R173L) variant is absent from large population studies (ExAC no frequency). The R173L was found in one family in female proband and her sister, and was absent in the proband's niece. The female proband is mildly affected and stable. Her sister has manifested with severe peripartum DCM and underwent heart transplantation (HT) at age 21. There are known 2 different substitutions at 173 codon (R173Q, R173W) which have been classified as Pathogenic (rs397516471, PMID: 22517884) due to high importance of p.Arg173. Evaluation of R173L in our clinical center has been done in silico with NetGene2, SpliceSite predictors, Provean, Sift, PolyPhen2. All calculations result in deleterious/damaging effect. Based on evidences the c.518G>T (R173L) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
CardioboostCm	Uncertain	0.72
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;.;.;.;D;.;.;.;.;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.;.;.
PhyloP100		4.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.4	D;D;.;D;.;.;.;.;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D;.;D;.;.;.;.;D;D;D
Sift4G	Benign	0.067	T;T;D;T;T;T;T;T;T;T;.
Polyphen		0.99, 0.99	.;.;.;.;D;.;.;.;.;.;D
Vest4		0.71
MutPred		0.47		.;.;.;.;Gain of ubiquitination at K186 (P = 0.0374);.;.;.;.;.;.;
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.45
gMVP		0.77
Mutation Taster		=0/100	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: rs397516471; hg19: chr1-201332476;