rs727504246

Positions:

• chr1-201363330-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.566C>T​(p.Ser189Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.30

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a region_of_interest Disordered (size 99) in uniprot entity TNNT2_HUMAN there are 38 pathogenic changes around while only 2 benign (95%) in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 1-201363330-G-A is Pathogenic according to our data. Variant chr1-201363330-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201363330-G-A is described in Lovd as [Pathogenic]. Variant chr1-201363330-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.566C>T	p.Ser189Phe	missense_variant	12/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.566C>T	p.Ser189Phe	missense_variant	12/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 2 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Ser179Phe variant in TNNT2 was identified by our study in one individual with familial hypertrophic cardiomyopathy. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ser179Phe variant in TNNT2 has been reported in 6 individuals with familial hypertrophic cardiomyopathy, segregated with disease in 6 affected relatives from a cosanguineous, two-generation family. One individual died suddenly at 17 years of age and was homozygous for the variant and the other 5 individuals were heterozygous for the variant (PMID: 11034944). This variant has been reported pathogenic and likely pathogenic in ClinVar and two individuals with this variant in the heterozygous state and with familial hypertrophic cardiomyopathy were reported in ClinVar (Variation ID: 177634). In summary, although additional studies are required to fully establish its clinical significance, the p.Ser179Phe variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PP1_Strong (Richards 2015). -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Dilated cardiomyopathy 1D Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2010

The Ser179Phe variant in TNNT2 has been reported in one consanguineous family wi th HCM where it was present in 2 heterozygous individuals with mild HCM and in 1 homozygous individual who died early due to a severe form of HCM (Ho 2000). Thi s variant has also been identified by our laboratory in 1 adult and 1 child with HCM, and was absent from large population studies. The Ser179Phe variant was pr edicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011), which strongly supports but does not prove that the Ser1 79Phe variant is pathogenic. In summary, this variant is likely to be pathogenic and causative for HCM, though evidence suggests a milder form when present in t he heterozygous state. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The p.S179F variant (also known as c.536C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 536. The serine at codon 179 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was first reported in a consanguineous family with a history of hypertrophic cardiomyopathy (HCM) and sudden death. Two heterozygous individuals presented with a mild form of HCM; the variant was present in the homozygous state in an individual with a severe phenotype (Ho CY et al., Circulation 2000 Oct; 102(16):1950-5). This variant has also been detected in individuals from additional HCM cohorts or cohorts submitted for HCM genetic testing (Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Burstein DS et al. Pediatr Res. 2021 May;89(6):1470-1476). Functional studies suggest this variant may impact protein function through increased calcium sensitivity and force development; however, the physiological relevance of this finding has not been fully elucidated (Messer AE et al., Arch. Biochem. Biophys. 2016; doi: 10.1016/j.abb.2016.03.027; Harada K et al. J Biol Chem. 2004 Apr;279(15):14488-95). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of the available evidence, this alteration is likely to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 24, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 177634). This missense change has been observed in individuals with clinical findings consistent with hypertrophic cardiomyopathy (HCM) , including a homozygous individual with severe HCM and HCM tested at a diagnostic laboratory (PMID: 11034944, 24033266, 27532257). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 179 of the TNNT2 protein (p.Ser179Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;.;D;.;.;.;.;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.5	.;.;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.7	D;D;.;.;.;.;.;.;D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D
Vest4		0.77
MutPred		0.37		.;.;.;.;Loss of phosphorylation at S189 (P = 0.0373);.;.;.;.;.;.;
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.55
gMVP		0.83

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: rs727504246; hg19: chr1-201332458;