chr2-178528273-C-T

Variant names:

• chr2-178528273-C-T
• rs112188483
• NM_001267550.2:c.107377+1G>A

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.107377+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: TTN NM_001267550.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 7.65
• Publications: 8 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]

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 2-178528273-C-T is Pathogenic according to our data. Variant chr2-178528273-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 196723.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.107377+1G>A		splice_donor_variant, intron_variant	Intron 361 of 362	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.107377+1G>A		splice_donor_variant, intron_variant	Intron 361 of 362	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.0000121 AC: 3 AN: 248508 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1461108 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 726780

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86114

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111602

Other (OTH) AF: 0.0000497 AC: 3 AN: 60362

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74456

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5 Uncertain:1

Dec 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM3_strong, PVS1 -

Aug 20, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Oct 05, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant for which RNA studies demonstrate alteration of normal gene transcription and expression (PMID: 28716623); Located in the M-band, a region of TTN for which truncating variants are significantly associated with autosomal recessive skeletal myopathies and also with autosomal dominant cardiomyopathy (PMID: 17444505, 32778822, 36637017); Reported in the heterozygous state in a patient with dilated cardiomyopathy who did not harbor a second TTN variant (PMID: 25589632); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32778822, 25214167, 32039858, 31691645, 28716623, 29435569, 35081925, 35177841, 34135346, 36761691, 36264615, 25589632, 17444505, 36637017) -

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 c.99673+1G>A variant in TTN, reported in the literature as c.107377+1G>A (NM_001267550.1), has been identified in the compound heterozygous state with truncating A-band variants in 3 individuals with limb girdle muscular dystrophy (LGMD) and 1 individual with mild progressive muscle weakness and dilated cardiomyopathy (DCM) and segregated with disease in 1 affected sibling. The heterozygous parents of these individuals were all reportedly unaffected (Harris 2017, Savarese 2018). It has been reported in the heterozygous state in 1 individual with DCM (Roberts 2015). It has also been identified in 3/248508 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID # 196723). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In addition, cDNA and Western blot analysis of patient cells demonstrated an impact to splicing (Harris 2017, Savarese 2018). Based on the available evidence, it is not clear if this variant is causative of autosomal dominant DCM, which is usually associated with truncating variants in the A-band. However, this variant meets criteria to be classified as pathogenic for autosomal recessive LGMD. ACMG/AMP criteria applied: PM3_Strong, PM2, PVS1_Moderate, PP1, PS3_Supporting. -

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

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 361 of 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 (rs112188483, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive TTN-related neuromuscular conditions or dilated cardiomyopathy (PMID: 25214167, 25589632, 28716623, 29435569, 35081925). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 196723). 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 dominant or 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, internal data). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

Sep 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:1

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. -

Cardiovascular phenotype Pathogenic:1

Jul 18, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.80182+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 188 of the TTN gene. Coding exon 188 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 nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant (also referred to as NM_001267550.1:c.107377+1G>A) has been reported to co-occur in trans and with phase unknown with other TTN truncating variants in unrelated and related individuals with skeletal myopathies with or without cardiac involvement and an individual from a dilated cardiomyopathy cohort (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Harris E et al. Neuromuscul Disord, 2017 Nov;27:1009-1017; Savarese M et al. JAMA Neurol, 2018 May;75:557-565; Savarese M et al. Genet Med, 2020 Dec;22:2029-2040). Functional studies have also indicated this variant to result in aberrant splicing (Harris E et al. Neuromuscul Disord, 2017 Nov;27:1009-1017). This alteration disrupts the canonical splice site and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. While loss of function variants in TTN are present in 1-3% of the general population, truncating variants (a category that includes canonical splice site 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		7.6
GERP RS		5.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs112188483; hg19: chr2-179393000; COSMIC: COSV108866237; COSMIC: COSV108866237;