rs397516466

chr1-201364341-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001276345.2(TNNT2):c.446G>A(p.Arg149His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 5.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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, 11 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 chr1-201364342-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2115456.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 1-201364341-C-T is Pathogenic according to our data. Variant chr1-201364341-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43642.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, Uncertain_significance=1}. Variant chr1-201364341-C-T is described in Lovd as [Pathogenic]. Variant chr1-201364341-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.446G>A	p.Arg149His	missense_variant	11/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.446G>A	p.Arg149His	missense_variant	11/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249998 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460846 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726778

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2022	Identified in patients with DCM in published literature (Morales et al., 2010; Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a decrease in calcium sensitivity, damaging protein function (Morales et al, 2010); 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: 27532257, 20973921, 29367539, 28352236, 21310275, 31521807, 33019804, 32880476, 33500567, 33906374) -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2023

The p.Arg139His variant in TNNT2 has been reported in at least 8 individuals with dilated cardiomyopathy (DCM), including 2 infants, and segregated with disease in at least 8 affected relatives from 2 families. However, this variant has also been found in unaffected relatives (in some individuals in their 50s) and in unaffected parents of infants with DCM (Morales 2010 PMID: 20973921, Millat 2014 PMID: 24721642, Li 2020 PMID: 31521807, Hey 2020 PMID: 33019804, Verdonschot 2020 PMID: 32880476, Ware 2021 PMID: 33906374, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43642) and has been identified in 0.00088% (1/113310) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant impacts protein function (Morales 2010 PMID: 20973921), and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant involving this codon (p.Arg139Cys) has been identified in individuals with DCM. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting. -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 139 of the TNNT2 protein (p.Arg139His). This variant is present in population databases (rs397516466, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20973921, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43642). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20973921). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 08, 2019

Variant summary: TNNT2 c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 244976 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.416G>A has been reported in the literature in individuals affected with Cardiomyopathy (Morales_2010, Pugh_2014, Walsh_2017). The initial publication by Morales et al (2010), reported the presence of this variant in cis with another intronic TNNT2 variant (c.690-6G>A) that the authors considered to be of unknown significance. However the estimated penetrance of Cardiomyopathy (0.33) due to this variant appears to be lower than expected (0.4), as the variant was also identified in the unaffected offspring of the proband with the same TNNT2 genotype (Morales_2010). Therefore, no conclusions can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in measures of maximal force of recovery in addition to desensitization of myofilaments to calcium at pH 6.5. However, the authors conclude that a 20% reduction in maximal force recovery represents a significant finding sufficient to explain the pathophysiology of late onset DCM brought on by fatty inflitration of the right ventricle (Morales_2010). Additional independent confirmation of these functional findings is awaited. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.4	D;D;D;.;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;.;D
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D;.
Vest4		0.77
MutPred		0.53		.;.;.;.;Loss of MoRF binding (P = 0.4322);.;.;.;.;.;.;Loss of MoRF binding (P = 0.4322);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.65
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516466; hg19: chr1-201333469;