ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs397517776
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Total submissions: 9
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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p.Arg30199fs variant in TTN has been identified in 1 individual with DCM and 1 individual with HCM (Herman 2012, LMM unpublished data).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,; 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 2021-12-17 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 (DCM) (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 2022-05-20 criteria provided, single submitter clinical testing 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; Not observed at a significant frequency in large population cohorts (gnomAD); Located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 30535219, 25589632, 30471092, 34088380, 35027292, 22335739)
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

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