2-178679958-CTCTTCT-CTCT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_001267550.2(TTN):c.33513_33515delAGA(p.Glu11172del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000942 in 1,613,002 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 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 1 hom. )

Consequence

TTN
NM_001267550.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 3.88

Publications

6 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	NM_001267550.2	MANE Select	c.33513_33515delAGA	p.Glu11172del	disruptive_inframe_deletion	Exon 140 of 363	NP_001254479.2
TTN	NM_001256850.1		c.32562_32564delAGA	p.Glu10855del	disruptive_inframe_deletion	Exon 138 of 313	NP_001243779.1
TTN	NM_133378.4		c.29781_29783delAGA	p.Glu9928del	disruptive_inframe_deletion	Exon 137 of 312	NP_596869.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTN	ENST00000589042.5	TSL:5 MANE Select	c.33513_33515delAGA	p.Glu11172del	disruptive_inframe_deletion	Exon 140 of 363	ENSP00000467141.1
TTN	ENST00000446966.2	TSL:1	c.33513_33515delAGA	p.Glu11172del	disruptive_inframe_deletion	Exon 140 of 361	ENSP00000408004.2
TTN	ENST00000436599.2	TSL:1	c.33237_33239delAGA	p.Glu11080del	disruptive_inframe_deletion	Exon 138 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000125

AC:

AN:

248470

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.0000873

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1460980

Hom.:

AF XY:

0.0000936

AC XY:

AN XY:

726794

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33444

American (AMR)

AF:

0.0000896

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000855

AC:

AN:

1111372

Other (OTH)

AF:

0.000199

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000151

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41502

American (AMR)

AF:

0.0000656

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000884

AC:

AN:

67910

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000368

Hom.:

Bravo

AF:

0.000204

EpiCase

AF:

0.000164

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:1

Mar 23, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 19, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23861362)

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 08, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Jan 02, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.29781_29783delAGA (p.Glu9928del) results in an in-frame deletion that is predicted to remove one amino acid from the I-band region of the encoded protein. The variant allele was found at a frequency of 0.00012 in 248470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00012 vs 0.00039), allowing no conclusion about variant significance. c.29781_29783delAGA has been reported in the literature in a cohort of individuals with a spectrum of coronary artery disease risk (Ng_2013), however without strong evidence for causality (e.g., lack of clinical and co-segregation data). This report therefore does 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. The following publication was ascertained in the context of this evaluation (PMID: 23861362). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (VUS, n = 3; likely benign, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over