ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.92317C>T (p.Arg30773Ter) (rs794729301)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184281 SCV000236904 pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing The R28205X pathogenic variant in the TTN gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge; however, other loss-of-function variants in the TTN gene have been reported in the Human Gene Mutation Database in association with TTN-related disorders (Stenson et al., 2014). The R28205X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Additionally, this variant is located in the A-band of the titin protein, where the majority of pathogenic truncating variants have been reported.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000184281 SCV000345809 likely pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619760 SCV000737193 likely pathogenic Cardiovascular phenotype 2020-10-08 criteria provided, single submitter clinical testing The p.R21708* variant (also known as c.65122C>T), located in coding exon 166 of the TTN gene, results from a C to T substitution at nucleotide position 65122. This changes the amino acid from an arginine to a stop codon within coding exon 166. This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med. 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med. 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet. 2017 Jan;49:46-53). As such, this alteration is classified as likely pathogenic.
Invitae RCV001212639 SCV001384228 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-09-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg30773*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with early-onset atrial fibrillation (PMID: 30535219). ClinVar contains an entry for this variant (Variation ID: 202424). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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