rs759525338

Positions:

• chr2-178621732-GCTT-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_001267550.2(TTN):​c.45089_45091del​(p.Glu15030del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000165 in 1,610,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TTN NM_001267550.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 6.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.45089_45091del	p.Glu15030del	inframe_deletion	245/363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.45089_45091del	p.Glu15030del	inframe_deletion	245/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.502+24060_502+24062del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000922 AC: 14 AN: 151832 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 37 AN: 243276 Hom.: 0 AF XY: 0.000167 AC XY: 22 AN XY: 132066

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000344

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 252 AN: 1458744 Hom.: 0 AF XY: 0.000164 AC XY: 119 AN XY: 725568

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000922 AC: 14 AN: 151832 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74134

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2014	c.40166_40168delAAG: p.Glu13389del (E13389del) in exon 195 of the TTN gene (NM_001256850.1). The c.40166_40168delAAG variant has not been published as a mutation or as a benign polymorphism to our knowledge. c.40166_40168delAAG results in deletion of Glutamic acid at position 13389 and does not cause a shift in reading frame. Only one in-frame deletion/duplication mutation in the TTN gene has been reported in association with tibial muscular dystrophy. Furthermore, c.40166_40168delAAG is not located in the A-band region of TTN, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 03, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 11, 2023

Variant summary: TTN c.37385_37387delAAG (p.Glu12462del) results in an in-frame deletion that is predicted to remove one amino acid that is located in the I-band region of the encoded protein. The variant allele was found at a frequency of 0.00015 in 243276 control chromosomes, predominantly at a frequency of 0.00034 and 0.00027 within the East Asian and European subpopulations, respectively (gnomAD database). These frequencies are somewhat lower than the maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (DCM) phenotype (0.00039). However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in the Swedish (allele frequency: 0.00052), suggesting that the variant might be a benign polymorphism. c.37385_37387delAAG has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual within a cohort with Pediatric Dilated Cardiomyopathy (example, Khan_2022). These report(s) 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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as uncertain significance (n=8) (LB, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2017

- -

Arrhythmogenic right ventricular dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 27, 2017

The TTN Glu13389del results in an in-frame deletion of a glutamine (Glu) at position 13389. We have identified this variant in a proband presenting with sudden cardiac death, they were diagnosed with ARVC at post-mortem. The proband has no family history of disease. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), at an allele frequency of 0.0002163, which is higher then expected for an inherited heart condition. The clinical consequence of TTN in-frame deletions are currently unknown. Therefore, we classify TTN Glu13389del as a variant of "uncertain significance" though this may be downgraded in future. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs759525338; hg19: chr2-179486459;