rs281864930

Positions:

chr2-178527098-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_001267550.2(TTN):c.107889del(p.Lys35963AsnfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TTN
NM_001267550.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 2.67

Variant links:

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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM4

Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 35971 codons.

PP5

Variant 2-178527098-GT-G is Pathogenic according to our data. Variant chr2-178527098-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 38439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178527098-GT-G is described in Lovd as [Likely_pathogenic]. Variant chr2-178527098-GT-G is described in Lovd as [Pathogenic]. Variant chr2-178527098-GT-G is described in Lovd as [Pathogenic]. Variant chr2-178527098-GT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.107889del	p.Lys35963AsnfsTer9	frameshift_variant	363/363	ENST00000589042.5	NP_001254479.2
TTN-AS1	NR_038272.1 linkuse as main transcript	n.219+3465del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.107889del	p.Lys35963AsnfsTer9	frameshift_variant	363/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.416+3465del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249174

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135174

show subpopulations

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727110

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Reported as g.293378delA in the heterozygous state in individuals from two Spanish families with tibial muscular dystrophy (TMD) (Hackman et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation as the last 29 amino acids are replaced with 8 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 20301498, 23975875, 18948003, 26627873, 26516846, 27854229, 24395473, 30238059, 31589614, 32528171, 32403337, 32039858) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -

Dilated cardiomyopathy 1G

Pathogenic:3

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	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 25, 2023	- -

TTN-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The TTN c.107889delA variant is predicted to result in a frameshift and premature protein termination (p.Lys35963Asnfs*9). This variant has been reported in individuals with tibial muscular dystrophy, centronuclear myopathy, dilated cardiomyopathy and sudden cardiac death (Hackman et al. 2008. PubMed ID: 18948003; Ceyhan-Birsoy et al. 2013. PubMed ID: 23975875; Evilä et al. 2014. PubMed ID: 24395473; Evilä et al. 2015. PubMed ID: 26627873; Campuzano et al. 2015. PubMed ID: 26516846). The c.107889delA variant is located in the M-band region of the TTN protein and other premature stop variants in this exon have previously been reported to be pathogenic for recessive and dominant TTN-related disorders (Human Gene Mutation Database). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%); however, this analysis in muscle tissue was not performed (Roberts A.M. et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). 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 O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, the c.107889delA variant is categorized as pathogenic for TTN-related disorders. -

Autosomal recessive limb-girdle muscular dystrophy type 2J

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

Dec 03, 2018

The heterozygous p.Lys35963AsnfsTer9 variant in TTN was identified by our study in the compound heterozygous state with a pathogenic variant in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with LGMD increases the likelihood that the p.Lys35963AsnfsTer9 variant is pathogenic. This variant has been identified in 0.001083% (3/277072) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs281864929). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 35963 and leads to a premature termination codon 9 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, the truncated protein region in the last exon includes the A-band (PMID: 26777568). This variant has also been reported in ClinVar (Variation ID: 38439). Loss of function of the TTN gene is an established disease mechanism in autosomal recessive LGMD. In summary, the p.Lys35963AsnfsTer9 variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PVS1_Strong, PM3, PM1 (Richards 2015). -

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 25, 2023

This sequence change creates a premature translational stop signal (p.Lys35963Asnfs*9) 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 (rs281864930, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive centronuclear myopathy, autosomal recessive tibial muscular dystrophy and/or dilated cardiomyopathy and atrial fibrillation (PMID: 23975875, 24395473, 26516846, 26627873, 34495297). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.K33395NfsX9. ClinVar contains an entry for this variant (Variation ID: 38439). 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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Autosomal recessive titinopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2023

Variant summary: TTN c.100185delA (p.Lys33395AsnfsX9) results in a premature termination codon within the last exon (M-band region, PSI 100%), predicted to cause a truncation of the encoded protein. The variant allele was found at a frequency of 4e-06 in 249174 control chromosomes (gnomAD). c.100185delA has been reported in the literature in multiple individuals affected with Autosomal Recessive Titinopathy and some individuals with a cardiac-related phenotype (e.g. Ceyhan-Birsoy_2013, Evila_2017, Gonzalez-Quereda_2020, Yoneda_2021, Barbosa-Gouveia_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35628876, 23975875, 27796757, 32403337, 34495297). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Tibial muscular dystrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Aug 23, 2012

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.80694delA pathogenic mutation, located in coding exon 190 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 80694, causing a translational frameshift with a predicted alternate stop codon (p.K26898Nfs*9). 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 mutation (also referred to as K33395Nfs*9 (c.100185delA), p.K35963Nfs*9 (c.107889delA), p.K33394Nfs*9 (c.100185delA) in the literature) has been reported in the homozygous and compound heterozygous state with other truncating variants in TTN in association with skeletal muscle disease phenotypes including distal myopathy, centronuclear myopathy, and tibial muscular dystrophy (Hackman P et al. Neuromuscul. Disord., 2008 Dec;18:922-8; Ceyhan-Birsoy O et al. Neurology, 2013 Oct;81:1205-14; Evilä A et al. Ann. Neurol., 2014 Feb;75:230-40; Evilä A et al. Neuromuscul. Disord., 2016 Jan;26:7-15; Välipakka S et al. Neurol Genet, 2017 Dec;3:e204). This variant has also been detected in sudden death and dilated cardiomyopathy cohorts; however, details were not provided (Campuzano O et al. Int J Mol Sci, 2015 Oct;16:25773-87). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear. -

Myopathy, myofibrillar, 9, with early respiratory failure

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as pathogenic and reported on 01/12/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over