ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.98299_98300del (p.Arg32767fs) (rs397517776)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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p.Arg30199fs variant in TTN has been identified in 1 individual with DCM and 1 individual with HCM (Herman 2012, LMM unpublished data).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; Limb-girdle muscular dystrophy, type 2J 2020-09-21 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides in exon 352 of the TTN mRNA (c.98299_98300delAG), causing a frameshift at codon 32767. This creates a premature translational stop signal (p.Arg32767Glyfs*2) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. Truncating variants in the A-band of TTN are likely pathogenic (PMID: 25589632). This particular truncation has been reported in several individuals affected with dilated cardiomyopathy (DCM) (PMID: 22335739, 25589632, Invitae). ClinVar contains an entry for this variant (Variation ID: 47599). This variant is also known as c.93376_93377delAG, p.Arg31126fs, in the literature. 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 2018-01-17 criteria provided, single submitter clinical testing The c.93376_93377delAG pathogenic variant in the TTN gene has been reported previously in a 63year-old female who was diagnosed with DCM at 53 years-old and had a positive family history; thisvariant was absent from 249 control subjects without known cardiomyopathy (Herman et al., 2012).The c.93376_93377delAG variant has also been seen in one other individual referred for DNA testingfor DCM at GeneDx. In addition, the c.93376_93377delAG variant was not observed inapproximately 6,100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. Thec.93376_93377delAG variant causes a shift in reading frame starting at codon Arginine 31126,changing it to a Glycine, and creating a premature stop codon at position 2 of the new reading frame,denoted p.Arg31126GlyfsX2. This pathogenic variant is expected to result in either an abnormal,truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay.Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman etal., 2012). However, c.93376_93377delAG is located in the A-band region of titin, where the majorityof truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012).In summary, c.93376_93377delAG in the TTN gene is interpreted as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000256132 SCV000702879 likely pathogenic not provided 2016-11-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286723 SCV001473337 likely pathogenic none 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.

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