rs397517776

Variant names:

• chr2-178539764-CCT-C
• rs397517776
• NM_001267550.2:c.98299_98300delAG

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.98299_98300delAG​(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.11
• Publications: 5 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: 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 47599.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.98299_98300delAG	p.Arg32767GlyfsTer2	frameshift_variant	Exon 352 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.98299_98300delAG	p.Arg32767GlyfsTer2	frameshift_variant	Exon 352 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152104 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248686 AF XY: 0.00000741

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461558 Hom.: 0 AF XY: 0.00000825 AC XY: 6 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111758

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jan 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 25, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 15, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Pathogenic:3

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. -

Feb 07, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 31, 2022

Center for Human Genetics, University of Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G Pathogenic:2

Aug 13, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 06, 2024

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:2

Sep 17, 2013

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4_mod, PM2 -

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

Jan 19, 2025

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.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; internal data). 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. -

SUDDEN INFANT DEATH SYNDROME Pathogenic:1

Oct 01, 2021

Robert's Program, Boston Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

May 02, 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.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’s 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397517776; hg19: chr2-179404491;