rs756433029

Variant names:

• chr2-178777234-CTTTCA-C
• rs756433029
• NM_001267550.2:c.4724_4728delTGAAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001267550.2(TTN):​c.4724_4728delTGAAA​(p.Met1575SerfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TTN NM_001267550.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17 U:2
• Conservation: PhyloP100: 9.25
• Publications: 5 publications found

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-178777234-CTTTCA-C is Pathogenic according to our data. Variant chr2-178777234-CTTTCA-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 202501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.4724_4728delTGAAA	p.Met1575SerfsTer6	frameshift_variant	Exon 27 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.4724_4728delTGAAA	p.Met1575SerfsTer6	frameshift_variant	Exon 27 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.4724_4728delTGAAA	p.Met1575SerfsTer6	frameshift_variant	Exon 27 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.4724_4728delTGAAA	p.Met1575SerfsTer6	frameshift_variant	Exon 27 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251014 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461794 Hom.: 0 AF XY: 0.0000261 AC XY: 19 AN XY: 727204

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Dec 30, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with DCM, LVNC and early-onset atrial fibrillation in patients tested at GeneDx and in published literature (PMID: 25589632, 30535219, 31112426, 31983221, 34540771, 36264615); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a region of a gene for which loss of function is not a well-established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30535219, 31983221, 34540771, 31112426, 36264615, 35177841, 33449170, 25589632, 37652022, 31691645) -

Jun 13, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: PVS1:Strong, PM2, PS4:Moderate -

Jan 16, 2025

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTN c.4724_4728del; p.Met1575SerfsTer6 variant (rs756433029, ClinVar Variation ID: 202501), is reported in the literature in individuals affected with dilated cardiomyopathy (Akhtar 2020, Jansen 2019, Mazzarotto 2020, Roberts 2015), in two individuals affected with centronuclear myopathy who also carried an additional truncating TTN variant (Rees 2021), an individual with early onset atrial fibril-lation (Choi 2018), and an individual with left ventricular noncompaction cardiomyopathy (Schultze-Berndt 2021). Additionally, this variant has been reported in general population controls (Choi 2020) and is observed on three allele in the Genome Aggregation Database (v2.1.1). This variant is in an exon that is spliced into 100% of TTN transcripts (Roberts 2015) and causes a frameshift by deleting 4 nucle-otides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on this information this variant is considered to be likely pathogenic. References: Akhtar MM et al. Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene. Circ Heart Fail. 2020 Oct;13(10):e006832. PMID: 32964742. Choi SH et al. DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consorti-um. Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. JAMA. 2018 Dec 11;320(22):2354-2364. PMID: 30535219. Choi SH et al. Monogenic and Polygenic Contributions to Atrial Fibrillation Risk: Results From a National Biobank. Circ Res. 2020 Jan 17;126(2):200-209. PMID: 31691645. Jansen M et al. Mortality Risk Associated With Truncating Founder Mutations in Titin. Circ Genom Precis Med. 2019 May;12(5):e002436. PMID: 31112426. Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circu-lation. 2020 Feb 4;141(5):387-398. PMID: 31983221. Rees M et al. Making sense of missense variants in TTN-related congenital myopathies. Acta Neuropa-thol. 2021 Mar;141(3):431-453. PMID: 33449170. Roberts AM et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015 Jan 14;7(270):270ra6. PMID: 25589632. Schultze-Berndt A et al. Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pe-diatric and Adult Left Ventricular Noncompaction Cardiomyopathy. Front Pediatr. 2021 Sep 3;9:722926. PMID: 34540771. -

Primary dilated cardiomyopathy Pathogenic:2

Oct 08, 2014

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. -

Feb 22, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met1575SerfsX6 variant in TTN has been reported in 1 individual with DCM (Roberts 2015) and has been identified in 3/128802 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID #202501). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1575 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Met1575SerfsX6 variant is located in a highly expressed exon in the near Z-disk region. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2. -

Dilated cardiomyopathy 1G Pathogenic:1 Uncertain:1

May 25, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3A. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a likely mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). Dominant disease are mostly associated with cardiomyopathy while recessive are associated with Salih myopathy and limb-girdle muscular dystrophy. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 28045975, PMID: 25589632). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 27 of 363). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (P) 0600 - Variant is located in an annotated domain or motif, (PSI = 100, near Z-disk; cardiacdb.org). (N) 0703 - Comparable variants also predicted to result in a NMD predicted protein have moderate previous evidence for pathogenicity (ClinVar, Decipher). However NMD variants causing dilated cardiomyopathy (DCM) are primarily located within the A band (PMID: 25589632) (P) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as both a VUS and as likely pathogenic (LOVD, ClinVar), but also within a DCM cohort (PMID: 25589632). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 – Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1

May 25, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TTN-related disorder Pathogenic:1

Sep 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TTN c.4724_4728del5 variant is predicted to result in a frameshift and premature protein termination (p.Met1575Serfs*6). This variant has been reported in a cohort study of individuals with dilated cardiomyopathy (Table S1, Roberts et al. 2015. PubMed ID: 25589632), as well as in one individual with early onset atrial fibrillation (eTable 5, Choi et al. 2018. PubMed ID: 30535219). This variant is located near the Z-disk and I-band junction. Other nearby loss-of-function variants have been reported in cases of autosomal recessive TTN-related myopathies (c.3880_3884delGATTC in Yu et al. 2019. PubMed ID: 31353864; c.4579delG in Töpf et al. 2020. PubMed ID: 32528171; c.4819G>T at PreventionGenetics). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals but occur more frequently in exons with low PSI values (Roberts et al. 2015. PubMed ID: 25589632; Herman et al. 2012. PubMed ID: 22335739). However, many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy et al. 2013. PMID: 23975875; Chauveau et al. 2014. PubMed ID: 24105469; Evilä et al. 2016. PubMed ID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, the c.4724_4728del variant is likely pathogenic for both autosomal recessive and dominant TTN-related disorders. -

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

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Met1575Serfs*6) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs756433029, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with centronuclear myopathy and/or dilated cardiomyopathy (PMID: 25589632, 30535219, 31112426, 31983221, 33449170; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 202501). This variant is located in the Z band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 33449170, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

May 08, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

May 25, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 9 Pathogenic:1

May 25, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction cardiomyopathy Pathogenic:1

-

Klaassen Lab, Charite University Medicine Berlin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Myopathy, myofibrillar, 9, with early respiratory failure Pathogenic:1

May 25, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tibial muscular dystrophy Pathogenic:1

May 25, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Mar 04, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4586_4590delTGAAA variant, located in coding exon 25 of the TTN gene, results from a deletion of 5 nucleotides at nucleotide positions 4586 to 4590, causing a translational frameshift with a predicted alternate stop codon (p.M1529Sfs*6). This exon is located in the near Z-disk region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant (also referred to as NM_001267550:c.4724_4728delTGAAA, p.Met1575Serfs*6) has been detected in individuals from dilated cardiomyopathy (DCM), left ventricular noncompaction, and early onset atrial fibrillation cohorts, as well as in individuals not known to have cardiovascular disease; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Choi SH et al. JAMA, 2018 12;320:2354-2364; Jansen M et al. Circ Genom Precis Med. 2019 May;12(5):e002436; Schultze-Berndt A et al. Front Pediatr. 2021 Sep;9:722926; Bourfiss M et al. Circ Genom Precis Med. 2022 Dec;15(6):e003704; Ambry internal data). This variant has also been detected in a proband with centronuclear myopathy (Rees M et al. Acta Neuropathol. 2021 Mar;141(3):431-453). This variant 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 (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; Akhtar MM et al. Circ Heart Fail, 2020 Oct;13:e006832; Massier M et al. Clin Genet, 2025 Jan). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs756433029; hg19: chr2-179641961;