ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186fs) (rs587780494)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118780 SCV000153341 pathogenic Tibial muscular dystrophy 2013-09-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725865 SCV000340085 uncertain significance not provided 2016-03-10 criteria provided, single submitter clinical testing
GeneDx RCV000298392 SCV000567763 uncertain significance not specified 2017-02-14 criteria provided, single submitter clinical testing A variant of uncertain significance was identified in the TTN gene. The c.6555_6556ins16 variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, the c.6555_6556ins16 variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant causes a shift in reading frame starting at codon Lysine 2186, changing it to a Cysteine, and creating a premature stop codon at position 15 of the new reading frame, denoted p.Lys2186CysfsX15. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, other truncating TTN variants have been reported in approximately 3% of control alleles, and c.6555_6556ins16 is not 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).
Ambry Genetics RCV000621565 SCV000737274 likely pathogenic Cardiovascular phenotype 2020-01-31 criteria provided, single submitter clinical testing The c.6417_6418ins16 variant, located in coding exon 27 of the TTN gene, results from an insertion of 16 nucleotides at position 6417, causing a translational frameshift with a predicted alternate stop codon (p.K2140Cfs*15). 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 (referred to as p.Lys2186fs) has been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA. 2018 12;320(22):2354-2364). 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). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae RCV000795260 SCV000934709 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2018-12-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Lys2186Cysfs*15). 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 ExAC database. This variant has been observed to segregate with dilated cardiomyopathy in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 130679). 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). 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.

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