NM_001267550.2:c.107635C>T

Variant names:

• chr2-178527491-G-A
• rs757082154
• NM_001267550.2:c.107635C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001267550.2(TTN):​c.107635C>T​(p.Gln35879*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000753 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TTN NM_001267550.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 U:1
• Conservation: PhyloP100: 6.56

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PP5: Variant 2-178527491-G-A is Pathogenic according to our data. Variant chr2-178527491-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527491-G-A is described in Lovd as [Pathogenic]. Variant chr2-178527491-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.107635C>T	p.Gln35879*	stop_gained	Exon 362 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.107635C>T	p.Gln35879*	stop_gained	Exon 362 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248904 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461646 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Aug 17, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with muscle weakness and reduced ejection fraction who also harbored an additional TTN loss of function variant, but phase was not reported (Savarese et al., 2018); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 113 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Located in the M-line region of the titin protein, where the majority of pathogenic truncating variants associated with autosomal recessive muscular dystrophy have been reported (Carmignac et al., 2007); This variant is associated with the following publications: (PMID: 32039858, 17444505, 32528171, 27796757, 29435569, 34935411, 28295036, 32778822, 34106991, 23975875) -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTN: PVS1, PM2, PM3, PS4:Supporting -

TTN-related disorder Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 03, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000202529, PMID:28295036). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Neuromuscular disease Pathogenic:1

Apr 12, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln33311X variant in TTN, reported in the literature as p.Gln35879X (NM_001267550.1), has been identified in the compound heterozygous or homozygous state in greater than 15 individuals with distal myopathy (Eliva 2017, Peric 2017, Savarese 2018). The majority of these individuals were Serbian, suggesting that this variant is likely a founder mutation in that population (Peric 2017). It has also been identified in 3/248904 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID # 202529). This nonsense variant leads to a premature termination codon at position 33311. This alteration occurs within the terminal 50 bases of the second to last exon and is therefore likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive distal myopathy. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP1. -

Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

-

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C2673677:Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

Oct 15, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PP5, PM2_P, PM3, PVS1; Variant was found in heterozygous state -

Myopathy;C1836296:Lower limb muscle weakness;C1853932:Rimmed vacuoles Pathogenic:1

Jan 04, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jun 04, 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.Gln35879*) 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 (rs757082154, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive TTN-related myopathy and/or dilated cardiomyopathy (PMID: 27796757, 28295036, 29435569, 34935411). This variant has been reported in individual(s) with clinical features of autosomal dominant TTN-related conditions (Invitae); however, the role of the variant in this condition is currently unclear. This variant is also known as c. 102712C>T (p.Gln34238*). ClinVar contains an entry for this variant (Variation ID: 202529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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, Invitae internal data). For these reasons, this variant has been classified as Pathogenic. -

Muscular dystrophy;C0231712:Waddling gait;C0686353:Limb-girdle muscular dystrophy;C1836767:Proximal lower limb amyotrophy;C3277184:Decreased patellar reflex Pathogenic:1

Feb 04, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lower limb muscle weakness Pathogenic:1

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Aug 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q26814* pathogenic mutation (also known as c.80440C>T), located in coding exon 189 of the TTN gene, results from a C to T substitution at nucleotide position 80440. This changes the amino acid from a glutamine to a stop codon within coding exon 189. This exon is located in the M-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 99%). This alteration occurs at the 3' terminus of theTTN gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 112AA of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration, which is also known as c.107635C>T p.Q35879*, has been reported in distal myopathy and limb girdle muscular dystrophy cohorts in multiple individuals as either homozygous or compound heterozygous with an additional alteration in TTN identified (Evilä A et al. Mol Neurobiol, 2017 Nov;54:7212-7223; Peri S et al. Eur J Hum Genet, 2017 May;25:572-581; Savarese M et al. JAMA Neurol, 2018 May;75:557-565). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear. -

TTN-related myopathy Pathogenic:1

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Gln35879Ter variant in TTN was identified by our study, in the compound heterozygous state with a likely pathogenic variant (NC_000002.12:g.178543072del), in one individual with limb-girdle muscular dystrophy. This individual also carried a likely pathogenic variant (NC_000002.12:g.178543072del), however the phase of these variants are unknown at this time. The p.Gln35879Ter variant in TTN has been previously reported in 16 unrelated individuals with TTN-related myopathy (PMID: 34106991, PMID: 29435569, PMID: 28295036) and segregated with disease in 2 affected relatives in one family (PMID: 34106991), but has been identified in 0.003% (1/34510) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs757082154). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 16 affected individuals (PMID: 34106991, PMID: 29435569, PMID: 28295036), 3 were homozygotes (PMID: 28295036) and 6 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 34106991, ClinVar Variation ID: 374145; PMID: 28295036, ClinVar Variation ID: 374145), which increases the likelihood that the p.Gln35879Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 202529) and has conflicting interpretations of pathogenicity. This nonsense variant leads to a premature termination codon at position 35879. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy 10. In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy 10. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3_VeryStrong (Richards 2015). -

Limb-girdle muscle atrophy;C1858127:Limb-girdle muscle weakness Uncertain:1

Oct 09, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	78
DANN	Benign	0.94
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.74
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs757082154; hg19: chr2-179392218;