rs1043395012

Variant names:

• chr2-178780092-C-G
• rs1043395012
• NM_001267550.2:c.3637G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001267550.2(TTN):​c.3637G>C​(p.Glu1213Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.20

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]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

LOC101927055 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24786547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.3637G>C	p.Glu1213Gln	missense_variant	Exon 22 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.3637G>C	p.Glu1213Gln	missense_variant	Exon 22 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.3637G>C	p.Glu1213Gln	missense_variant	Exon 22 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.3637G>C	p.Glu1213Gln	missense_variant	Exon 22 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1

May 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Jul 06, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1167Q variant (also known as c.3499G>C), located in coding exon 20 of the TTN gene, results from a G to C substitution at nucleotide position 3499. The glutamic acid at codon 1167 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Benign	0.97
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;.;T;T;T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N;N;.;.;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.11	T;T;.;.;T;T;.;T
Sift4G	Uncertain	0.014	.;.;.;.;.;.;.;D
Polyphen		0.023, 0.66	.;.;.;B;.;.;B;P
Vest4		0.13
MutPred		0.34		Gain of methylation at K1216 (P = 0.0643);.;Gain of methylation at K1216 (P = 0.0643);Gain of methylation at K1216 (P = 0.0643);.;.;Gain of methylation at K1216 (P = 0.0643);Gain of methylation at K1216 (P = 0.0643);
MVP		0.20
MPC		0.087
ClinPred		0.44	T
GERP RS		5.7

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: rs1043395012; hg19: chr2-179644819; COSMIC: COSV60108646; COSMIC: COSV60108646;