ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.75134_75137AGAA[1] (p.Lys25046fs) (rs794729340)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184330 SCV000236955 likely pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing Although the c.70215_70218delAGAA mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Lysine 23405, changing it to an Asparagine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Lys23405AsnfsX8. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.70215_70218delAGAA is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, c.70215_70218delAGAA in the TTN gene is interpreted as a disease-causing mutation.
Baylor Genetics RCV000680140 SCV000807584 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Myopathy, early-onset, with fatal cardiomyopathy; Familial hypertrophic cardiomyopathy 9 2017-09-01 criteria provided, single submitter clinical testing This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory In trans with a missense variant (W7053C) in an 8-year-old male with congenital myopathy, hypotonia, hyperextensibility, scapular winging, weakness, joint laxity, ankle contractures, type I fiber predominance on muscle biopsy, family history of a brother with a similar phenotype (also compound heterozygous)
Invitae RCV001203442 SCV001374608 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-10-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Lys25046Asnfs*8). 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related conditions. 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). 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.

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