rs397517776

Positions:

chr2-178539764-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001267550.2(TTN):c.98299_98300del(p.Arg32767GlyfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000806 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R32767R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TTN
NM_001267550.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.11

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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-178539764-CCT-C is Pathogenic according to our data. Variant chr2-178539764-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 47599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178539764-CCT-C is described in Lovd as [Likely_pathogenic]. Variant chr2-178539764-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.98299_98300del	p.Arg32767GlyfsTer2	frameshift_variant	352/363	ENST00000589042.5
TTN-AS1	NR_038272.1 linkuse as main transcript	n.1715_1716del		non_coding_transcript_exon_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.98299_98300del	p.Arg32767GlyfsTer2	frameshift_variant	352/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.416+16129_416+16130del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152104

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248686

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134898

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461558

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

727062

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:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	The TTN c.98299_98300del; p.Arg32767fs variant (rs397517776), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 47599). This variant is listed in the Genome Aggregation Database (gnomAD) identified on 2 chromosomes out of 280,078. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Moreover, this variant is in the A-band, a zone in the TTN protein disproportionately enriched with truncating variants in patients diagnosed with dilated cardiomyopathy (Roberts, 2015). Overall, the p.Arg32767fs variant meets our criteria for likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); Also known as c.93376_93377delAG due to the use of an alternate transcript; This variant is associated with the following publications: (PMID: 30535219, 25589632, 30471092, 34088380, 22335739, 23975875, 33106378, 34495297, 35027292) -

Primary dilated cardiomyopathy

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 07, 2022	The p.Arg30199fs variant in TTN has been identified in 1 individual with DCM and 1 individual with HCM (Herman 2012, LMM unpublished data). This variant has also been identified in 2/126166 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs397517776). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 30199 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift 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). The p.Arg30199fs variant is located in the A-band in the highly expressed exon 301. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg30199fs variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Dec 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	Oct 08, 2014	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. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change creates a premature translational stop signal (p.Arg32767Glyfs*2) 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 (rs397517776, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 22335739, 25589632; Invitae). This variant is also known as c.93376_93377delAG (p.Arg31126fs). ClinVar contains an entry for this variant (Variation ID: 47599). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1G

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Aug 13, 2019

This TTN variant (c.98299_98300delAG) deletes two nucleotides and is predicted to cause a frameshift and subsequent premature stop codon (p.Arg32767GlyfsTer2) leading to a shortened or absent protein. This variant is located in the A-band of TTN where other pathogenic truncating variants have been described in individuals with DCM (PMID: 25589632). It is present at very low frequency (2/280078) in gnomAD. In addition, it has been described in several individuals with DCM (PMID: 22335739, 25589632). It is therefore considered a pathogenic variant. -

SUDDEN INFANT DEATH SYNDROME

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Robert's Program, Boston Children's Hospital

Oct 01, 2021

We classify this variant as pathogenic using the following ACMG/AMP criteria: PVS1, PM1, PP5 -

Early-onset myopathy with fatal cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

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

May 02, 2023

The heterozygous p.Arg32767GlyfsTer2 variant in TTN was identified by our study, in the compound heterozygous state with a likely variant (ClinVar Variation ID: 489358), in two affected siblings with Salih myopathy. Familial genome analysis confirmed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 489358), which increases the likelihood that the p.Arg32767GlyfsTer2 variant is pathogenic. The p.Arg32767GlyfsTer2 variant has not been previously reported in individuals with Salih myopathy but has been identified in 0.0015% (2/127958) European (non-Finnish) chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs995110630). 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. This variant has also been reported in ClinVar (Variation ID: 47599) and has been interpreted as pathogenic by Invitae, GeneDx, Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, Robert's Program,Boston Children's Hospital and as likely pathogenic by Eurofins NTD LLC (GA), ARUP Laboratories, Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust, Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine, and Ambry Genetics, albeit for other forms of TTN-related disease. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 32767 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism of autosomal recessive Salih myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Salih myopathy. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting (Richards 2015). -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2013

The c.90595_90596delAG variant, located in coding exon 300 of the TTN gene, results from a deletion of 2 nucleotides between positions 90595 and 90596, causing a translational frameshift with a predicted alternate stop codon. Frameshift alterations resulting in a truncated protein substantially alter protein structure, and this variant therefore meets ACMG criteria for classification as a mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). Furthermore, truncating alterations in TTN were observed at a significantly higher frequency among patients with dilated cardiomyopathy (DCM), or 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3/231, 1%, P=9x10-14) and healthy controls (7 of 247, 3%, P=4x10-5). Among families with multiple relatives with DCM, this study also provided strong data demonstrating segregation with disease (Herman et al. 2012 NEJM 366:619-628). However, the functional consequence of protein truncating alterations in TTN have not been well described, and this specific alteration (TTN c.90595_90596delAG) has not been reported in the literature. Therefore, this variant is likely to be pathogenic; however, due to the uncertainty of the functional and clinical consequences, its significance remains unclear. -

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