ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.85969A>T (p.Lys28657Ter)

dbSNP: rs72648224
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000821629 SCV000962398 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-02-24 criteria provided, single submitter clinical testing This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 22335739). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys28657*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. ClinVar contains an entry for this variant (Variation ID: 663697). 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. 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).
New York Genome Center RCV003227866 SCV003925279 pathogenic Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9 2022-01-25 criteria provided, single submitter clinical testing The c.85969A>T (p.Lys28657Ter) variant identified in the TTN gene is a nonsense variant that leads to the premature termination of the protein at amino acid 28657/35991 (exon 326/363) and is expected to result in either an abnormal, truncated protein product or loss of protein through nonsense-mediated mRNA decay. This variant is absent from gnomAD (v2.1.1 and v3.1.2) suggesting it is not a common benign variant in the populations represented in that database.This variant is reported as Likely Pathogenic in ClinVar (Variation ID: 663697) database and has been reported in multiple individuals affected with dilated cardiomyopathy in the literature (PMID: 22335739, 31514951, 24119082). The p.Lys28657 residue is located in the A-band domain of TTN protein (PMID: 25589632), where most variants associated with dilated cardiomyopathy are located (PMID: 32964742, 26777568, 27869827, 28045975, 25589632). The c.85969A>T(p.Lys28657Ter) variant identified in the TTN gene is reported as Pathogenic.

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