ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.94344_94347del (p.Lys31448fs)

dbSNP: rs727503546
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000152183 SCV000200920 likely pathogenic Primary dilated cardiomyopathy 2017-05-16 criteria provided, single submitter clinical testing The p.Lys28880fs variant in TTN has been previously reported in 1 individual wit h DCM and segregated with disease in 3 affected relatives (Norton 2013). In addi tion, it has been identified by our laboratory in 1 adult with DCM and segregate d with disease in another affected family member. The variant has not been ident ified in large population studies. It is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 28880 and leads t o a premature termination codon 8 amino acids downstream. This alteration is the n predicted to lead to a truncated or absent protein. Frameshift and other trunc ating variants in TTN are strongly associated with DCM, particularly if they are located in the exons encoding for the A-band region of the protein (Herman 2012 , Pugh 2014), where this variant is located. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Lys28880fs variant is likely pathogenic for autosomal dominant DCM based on the segregatio n evidence and its predicted impact to the protein.
GeneDx RCV001582623 SCV001814100 pathogenic not provided 2024-07-18 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31514951, 31737537, 35276540, 23418287, 36396199)
AiLife Diagnostics, AiLife Diagnostics RCV001582623 SCV002501434 pathogenic not provided 2021-09-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003764930 SCV004568984 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys31448Asnfs*8) in the TTN gene. 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 (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 23418287, 31514951, 31737537). It has also been observed to segregate with disease in related individuals. This variant is also known as Lys28880AsnfsX8. ClinVar contains an entry for this variant (Variation ID: 165719). 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). For these reasons, this variant has been classified as Pathogenic.
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere RCV004764902 SCV005375068 likely pathogenic Dilated cardiomyopathy 1G 2024-01-06 no assertion criteria provided clinical testing

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