ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.12316C>T (p.Gln4106Ter)

dbSNP: rs1553940122
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000642815 SCV000764502 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-04-28 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). ClinVar contains an entry for this variant (Variation ID: 535052). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 31514951, 31983221, 33500567). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln4106*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017705 SCV004848557 likely pathogenic Primary dilated cardiomyopathy 2021-09-13 criteria provided, single submitter clinical testing The p.Gln3868X variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 3868, which is predicted to lead to a truncated or absent protein. This alteration occurs in the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. TTN truncating variants encoded in constitutive exons (PSI >95%) have been found to be significantly associated with DCM regardless of their position in titin (Roberts 2015 PMID:25589632, Schafer 2017 PMID:27869827). This variant is located in such a highly expressed exon in the I-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.
Ambry Genetics RCV004025646 SCV005020365 likely pathogenic Cardiovascular phenotype 2023-12-15 criteria provided, single submitter clinical testing The p.Q3743* variant (also known as c.11227C>T), located in coding exon 44 of the TTN gene, results from a C to T substitution at nucleotide position 11227. This changes the amino acid from a glutamine to a stop codon within coding exon 44. 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 has been reported in association with dilated cardiomyopathy (DCM) (Gigli M et al. J Am Coll Cardiol, 2019 Sep;74:1480-1490). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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