chr1-201365244-A-G

Variant names:

• chr1-201365244-A-G
• rs121964858
• NM_001276345.2:c.358T>C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Moderate PP5

The NM_001276345.2(TNNT2):​c.358T>C​(p.Phe120Leu) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F120V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• 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]

ENSG00000286600 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PS1: Transcript NM_001276345.2 (TNNT2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 177807
• 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 chr1-201365244-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 12412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 1-201365244-A-G is Pathogenic according to our data. Variant chr1-201365244-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235064.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.358T>C	p.Phe120Leu	missense_variant	Exon 10 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.358T>C	p.Phe120Leu	missense_variant	Exon 10 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Feb 21, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TNNT2 variant Phe110Leu (F110L; T>C at the nucleotide level) This variant has been reported in at least 2 unrelated cases of HCM, with segregation data available from one family. Toricelli et al. (2003) first reported Phe110Leu in an HCM patient from Tuscany. The variant segregated with disease in a proband, her mother, and her maternal grandfather. Olivotto et al. (2008) appear to be referring to that same proband. Girolami et al. (2006) detected the variant in another Italian proband. Other changes at codon 110 have also been associated with disease: Phe110Ile (which we classify as very likely disease causing) and Phe110Val (which we classify as of uncertain significance, probably disease causing). Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. This includes Ala104Val (HCM) and Arg113Trp (DCM) (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). In vitro functional data from Palm et al. (2001) suggests that a change at codon 110—specifically Phe110Ile—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. This is a conservative amino acid change from a nonpolar Phenylalanine to a nonpolar Leucine (with a smaller side-chain). The Phenylalanine at codon 110 is completely conserved across 39 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In total the variant has not been seen in ~5550 published controls and publicly available population datasets. There is no variation at codon 110 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Toricelli et al. (2003) did not find Phe110Leu in 150 healthy controls from Tuscany. Girolami et al. (2006) did not find it in 100 Italian controls. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.;.;.;.;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;.;D;.;.
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.7	D;D;.;.;.;.;.;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;D;D;D
Sift4G	Benign	0.065	T;T;T;T;T;D;T;T;.;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;D;.
Vest4		0.91
MutPred		0.39		.;.;.;Loss of methylation at K125 (P = 0.0775);.;.;.;.;.;Loss of methylation at K125 (P = 0.0775);
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.98

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: rs121964858; hg19: chr1-201334372;