rs397516454

Variant names:

• chr1-201365610-A-C
• rs397516454
• NM_001276345.2:c.294T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-201365610-A-C
• chr1-201365610-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.294T>G​(p.Asp98Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense, splice_region
• Scores: Splicing: ADA: 0.00004981
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.573
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 23 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
• PP5: Variant 1-201365610-A-C is Pathogenic according to our data. Variant chr1-201365610-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.294T>G	p.Asp98Glu	missense_variant, splice_region_variant	Exon 9 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.294T>G	p.Asp98Glu	missense_variant, splice_region_variant	Exon 9 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Jan 28, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33025817, 32458740) -

Primary dilated cardiomyopathy Pathogenic:1

Jun 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp88Glu variant in TNTT2 has been identified by our laboratory in 1 Cauca sian infant with DCM but not in large population studies. This variant is locate d in the last base of the exon, which is part of the 5' splice region. Computati onal tools do not suggest an impact to splicing. However, this information is no t predictive enough to rule out pathogenicity. Aspartic acid (Asp) at position 8 8 is highly conserved in mammals and across evolutionarily distant species and t he change to glutamic acid (Glu) was predicted to be pathogenic using a computat ional tool clinically validated by our laboratory. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). In summary, altho ugh additional studies are required to fully establish its clinical significance , the p.Asp88Glu variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;.;.;.;D;.;.;.;.;.;T;.;.;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;D;D;T;D;D;D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.9	.;.;.;.;M;.;.;.;.;.;.;.;.;.
PhyloP100		0.57
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D;D;.;.;.;.;.;.;D;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.060	T;T;.;.;.;.;.;.;T;T;T;D;D;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;.;T;T;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D;.;.;.
Vest4		0.59
MutPred		0.30		.;.;.;.;Loss of stability (P = 0.1561);.;.;.;.;.;.;Loss of stability (P = 0.1561);.;.;
MVP		0.93
MPC		1.4
ClinPred		0.99	D
GERP RS		-3.6
Varity_R		0.38
gMVP		0.94
Mutation Taster		=33/67	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.32
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: rs397516454; hg19: chr1-201334738;