rs752697861

Positions:

• chr2-178534092-G-A
• chr2-178534092-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001267550.2(TTN):​c.102523C>T​(p.Arg34175Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,640 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TTN NM_001267550.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.48

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-178534092-G-A is Pathogenic according to our data. Variant chr2-178534092-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178534092-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-178534092-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.102523C>T	p.Arg34175Ter	stop_gained	358/363	ENST00000589042.5	NP_001254479.2
TTN-AS1	NR_038272.1	n.220-1640G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.102523C>T	p.Arg34175Ter	stop_gained	358/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.416+10456G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248864 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135004

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461640 Hom.: 0 Cov.: 39 AF XY: 0.00000413 AC XY: 3 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TTN-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2024

The TTN c.102523C>T variant is predicted to result in premature protein termination (p.Arg34175*). This variant occurs within the M-band region of the titin protein. 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). Truncating TTN variants in constitutive exons (PSI > 90%) are significantly associated with dilated cardiomyopathy (DCM) irrespective of their position in TTN (Schafer et al. 2017. PubMed ID: 27869827). ACMG recommends reporting TTN truncating variants in highly expressed exons due to the significant risk of cardiomyopathy (see ACMG statement in Miller et al. 2021. PubMed ID: 34012068). TTN truncating variants show incomplete and age-dependent penetrance in relation to autosomal dominant dilated cardiomyopathy. This variant has been reported in the heterozygous state in multiple unrelated individuals with dilated cardiomyopathy (Table S2, Haskell et al. 2017. PubMed ID: 28611029; Table 2, Anderson et al. 2020. PubMed ID: 32998006; Supplementary Table IV, Bourfiss et al. 2022. PubMed ID: 36264615). This variant has also been reported in the compound heterozygous state in an individual presenting with congenital core myopathy combined with primary heart disease and in two siblings with rigid spine syndrome and respiratory difficulty (Chauveau et al. 2014. PubMed ID: 24105469; Park et al. 2017. PubMed ID: 27868403). 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. PubMed ID: 23975875; Chauveau et al. 2014. PubMed ID: 24105469; Evilä et al. 2016. PubMed ID: 27796757; Ge et al. 2019. PubMed ID: 31053406). Taken together, the c.102523C>T (p.Arg34175*) variant is interpreted as likely pathogenic for recessive and dominant TTN-related disorders. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change creates a premature translational stop signal (p.Arg34175*) 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 (rs752697861, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy, congenital myopathy, and/or muscular dystrophy with scoliosis (PMID: 24105469, 25163546, 27868403, 28611029, 32998006, 36264615). This variant is also known as c.C75904T, p.R25302X. ClinVar contains an entry for this variant (Variation ID: 464497). 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). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1G Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere

Jan 06, 2024

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 25, 2017

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The p.R25110* variant (also known as c.75328C>T), located in coding exon 185 of the TTN gene, results from a C to T substitution at nucleotide position 75328. This changes the amino acid from an arginine to a stop codon within coding exon 185. 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 100%).This variant (also referred to as p.Arg34175*) has been reported to co-occur with two other presumed truncating variants in TTN in individuals with childhood-onset skeletal myopathy with and without cardiomyopathy (Chauveau C et al. Hum Mol Genet, 2014 Feb;23:980-91; Park HJ et al. J Clin Neurol, 2017 Jan;13:116-118). This variant has also been detected in the presumed heterozygous state in an individual with dilated cardiomyopathy and in cohorts not selected for the presence of skeletal myopathy or cardiovascular disease; however, details were limited (Haggerty CM et al. Circulation. 2019 Jul;140(1):42-54; Haskell GT et al. Circ Cardiovasc Genet, 2017 Jun;10; Park J et al. Nat Med. 2021 Jan;27(1):66-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 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 likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	68
DANN	Benign	0.95
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.78
GERP RS		4.2

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

LitVar

Other links and lift over

dbSNP: rs752697861; hg19: chr2-179398819; COSMIC: COSV59993751; COSMIC: COSV59993751;