rs763098227

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBP6

The NM_001267550.2(TTN):c.34663_34665del(p.Glu11555del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000411 in 1,597,886 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 1 hom. )

Consequence

TTN
NM_001267550.2 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 3.93

Variant links:

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 links:

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]

TTN-AS1 links:

LOC124906100 (HGNC:):

LOC124906100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 2-178674356-GTTC-G is Benign according to our data. Variant chr2-178674356-GTTC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284097.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.34663_34665del	p.Glu11555del	inframe_deletion	151/363	ENST00000589042.5
LOC124906100	XR_007087318.1 linkuse as main transcript	n.2185+29860_2185+29862del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.34663_34665del	p.Glu11555del	inframe_deletion	151/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.503-60143_503-60141del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000257

AC:

AN:

151610

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000502

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000140

AC:

AN:

236262

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

127668

show subpopulations

Gnomad AFR exome

AF:

0.0000683

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:

0.000292

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000427

AC:

618

AN:

1446158

Hom.:

AF XY:

0.000420

AC XY:

302

AN XY:

718366

show subpopulations

Gnomad4 AFR exome

AF:

0.0000907

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000532

Gnomad4 OTH exome

AF:

0.000436

GnomAD4 genome

AF:

0.000257

AC:

AN:

151728

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000502

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000283

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TTN: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2019	In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not located in the A-band nor the M-line region of titin, where the majority of pathogenic truncating variants have been reported; Identified in a patient with hypertrophic cardiomyopathy in published literature (Sanchez et al., 2016); This variant is associated with the following publications: (PMID: 27930701) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2017

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 06, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 30, 2021

Variant summary: TTN c.30760_30762delGAA (p.Glu10254del) results in an in-frame deletion that is predicted to remove one amino acid from I-band domain of the encoded protein. The variant allele was found at a frequency of 0.00026 in 151610 control chromosomes, predominantly at a frequency of 0.0005 within the Non-Finnish European subpopulation in the gnomAD database (gnomAD v3). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.30760_30762delGAA has been reported in the literature in one individual affected with Hypertrophy Cardiomyopathy and one individual who was tested for Cardiomyopathy panel and without specified phenotype (Sanchez_2016, Fedida_2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over