rs727503704

Positions:

• chr2-178793441-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001267550.2(TTN):​c.1499C>T​(p.Thr500Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.524

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03980893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.1499C>T	p.Thr500Ile	missense_variant	9/363	ENST00000589042.5
TTN	NM_133379.5	c.1499C>T	p.Thr500Ile	missense_variant	9/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.1499C>T	p.Thr500Ile	missense_variant	9/363	5	NM_001267550.2	P1
TTN	ENST00000360870.10	c.1499C>T	p.Thr500Ile	missense_variant	9/46	5	NM_133379.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2014

Variant classified as Uncertain Significance - Favor Benign. The Thr500Ile varia nt in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. Threonine (Thr) at position 500 is not conserved i n mammals or evolutionarily distant species and rat carries an isoleucine (Ile), supporting that this change may be tolerated. Additional computational predicti on tools suggest that the Thr500Ile variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. In summary, although these data support that the Thr500Ile variant may be benign, additional studies are needed to fully assess its clinical significance. -

TTN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2023

The TTN c.1499C>T variant is predicted to result in the amino acid substitution p.Thr500Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.78
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.71	T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.040	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;.;.;N;N;.;N;D
REVEL	Benign	0.067
Sift	Benign	0.24	T;T;.;.;T;T;.;T;T
Sift4G	Benign	0.16	.;.;.;.;.;.;.;T;.
Polyphen		0.0, 0.0010	.;.;.;B;.;.;B;B;.
Vest4		0.30
MutPred		0.38		Gain of methylation at K502 (P = 0.0745);Gain of methylation at K502 (P = 0.0745);Gain of methylation at K502 (P = 0.0745);Gain of methylation at K502 (P = 0.0745);Gain of methylation at K502 (P = 0.0745);Gain of methylation at K502 (P = 0.0745);Gain of methylation at K502 (P = 0.0745);Gain of methylation at K502 (P = 0.0745);.;
MVP		0.099
MPC		0.090
ClinPred		0.030	T
GERP RS		0.022

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs727503704; hg19: chr2-179658168;