Submissions for variant NM_001267550.2(TTN):c.98299_98300del (p.Arg32767fs)

gnomAD frequency: 0.00002  dbSNP: rs397517776

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000209003	SCV000064559	likely pathogenic	Primary dilated cardiomyopathy	2017-08-07	criteria provided, single submitter	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p.Arg30199fs variant in TTN has been identified in 1 individual with DCM and 1 individual with HCM (Herman 2012, LMM unpublished data).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 als o been identified in 2/126166 European chromosomes by the Genome Aggregation Dat abase (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs397517776). This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 30199 and leads to a premature termination codon 2 a mino 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 201 2, Pugh 2014) and/or are located in an exon that is highly expressed in the hear t (Roberts 2015). The p.Arg30199fs variant is located in the A-band in the highl y expressed exon 301. In summary, although additional studies are required to fu lly establish its clinical significance, the p.Arg30199fs variant is likely path ogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209003	SCV000189709	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	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.
Invitae	RCV000231491	SCV000286949	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-16	criteria provided, single submitter	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; 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.
Ambry Genetics	RCV000248692	SCV000318979	likely pathogenic	Cardiovascular phenotype	2013-09-17	criteria provided, single submitter	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.
GeneDx	RCV000256132	SCV000322334	pathogenic	not provided	2023-01-13	criteria provided, single submitter	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)
Eurofins Ntd Llc (ga)	RCV000256132	SCV000702879	likely pathogenic	not provided	2016-11-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000256132	SCV001473337	likely pathogenic	not provided	2019-09-25	criteria provided, single submitter	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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001537859	SCV001754794	pathogenic	Dilated cardiomyopathy 1G	2019-08-13	criteria provided, single submitter	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.
Robert's Program, Boston Children's Hospital	RCV001787842	SCV002030074	pathogenic	SUDDEN INFANT DEATH SYNDROME	2021-10-01	criteria provided, single submitter	research	We classify this variant as pathogenic using the following ACMG/AMP criteria: PVS1, PM1, PP5
Center for Human Genetics, University of Leuven	RCV000209003	SCV002817409	pathogenic	Primary dilated cardiomyopathy	2022-12-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225927	SCV003922161	pathogenic	Early-onset myopathy with fatal cardiomyopathy	2023-05-02	criteria provided, single submitter	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).