rs727503559

chr2-178565119-TTTGGCAGCCACCAGTA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001267550.2(TTN):c.80997_81012del(p.Tyr26999Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y26999Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTN NM_001267550.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.94

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-178565119-TTTGGCAGCCACCAGTA-T is Pathogenic according to our data. Variant chr2-178565119-TTTGGCAGCCACCAGTA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 165810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178565119-TTTGGCAGCCACCAGTA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.80997_81012del	p.Tyr26999Ter	frameshift_variant	326/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2044-17451_2044-17436del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.80997_81012del	p.Tyr26999Ter	frameshift_variant	326/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-32475_417-32460del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1G Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 03, 2016	This sequence change deletes 16 nucleotides from exon 326 of the TTN mRNA (c.80997_81012del16), causing a frameshift at codon 26999. This creates a premature translational stop signal (p.Tyr26999*) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 11, 2023	The TTN c.80997_81012del (p.Tyr26999Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant is located in exon 326 of the meta transcript of titin within the A-band, which is highly expressed in cardiac tissue (PMID: 25589632). In a meta-analysis of TTN truncating variants in individuals with dilated cardiomyopathy (DCM) and controls, variants in this region were associated with a significantly increased risk of developing DCM (odds ratio 49.8) (PMID: 27869827). This variant has been previously identified in at least one individual with non-ischemic DCM (PMID: 32998006). This variant has not been observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as likely pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.80997_81012del (p.Tyr26999Ter) variant is classified as likely pathogenic for dilated cardiomyopathy. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). ClinVar contains an entry for this variant (Variation ID: 165810). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 32998006). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr26999*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 26, 2017

- -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 07, 2013

The Tyr24431X variant in TTN has not been reported in individuals with cardiomyo pathy. Data from large population studies is insufficient to assess the frequenc y of this variant. This nonsense variant results from a 16 base deletion and is predicted to lead to a truncated or absent protein. Nonsense and other truncatin g variants in TTN are strongly associated with DCM and the majority occur in the A-band (Herman 2012, LMM unpublished data), where this variant is located. In s ummary, this variant is likely to be pathogenic, though additional studies are r equired to fully establish its clinical significance. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2020

The c.53802_53817del16 variant, located in coding exon 153 of the TTN gene, results from a deletion of 16 nucleotides at nucleotide positions 53802 to 53817. This changes the amino acid at position 17934 from a tyrosine to a stop codon (p.Y17934*). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727503559; hg19: chr2-179429846;