ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.44035C>T (p.Arg14679Ter)

dbSNP: rs776970935
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000692897 SCV000820746 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg14679*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with centronuclear myopathy (PMID: 33449170). This variant has been reported in individual(s) with dilated cardiomyopathy (Invitae); however, the role of the variant in this condition is currently unclear. This variant is also known as c.44260C>T. ClinVar contains an entry for this variant (Variation ID: 571684). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). 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.
Ambry Genetics RCV002406576 SCV002715300 likely pathogenic Cardiovascular phenotype 2021-09-21 criteria provided, single submitter clinical testing The p.R5614* variant (also known as c.16840C>T), located in coding exon 65 of the TTN gene, results from a C to T substitution at nucleotide position 16840. This changes the amino acid from an arginine to a stop codon within coding exon 65. This exon is located in the I-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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 01;49:46-53). As such, this alteration is classified as likely pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003486918 SCV004239907 likely pathogenic Cardiomyopathy 2023-03-29 criteria provided, single submitter clinical testing

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