Submissions for variant NM_001267550.2(TTN):c.91097_91100del (p.Arg30366fs)

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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	RCV001214186	SCV001385857	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-03-23	criteria provided, single submitter	clinical testing	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). ClinVar contains an entry for this variant (Variation ID: 943903). This variant has not been reported in the literature in individuals affected with TTN-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg30366Ilefs*24) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Genetics and Genomics Program, Sidra Medicine	RCV001293218	SCV001434216	likely pathogenic	Primary dilated cardiomyopathy		criteria provided, single submitter	research
GeneDx	RCV003332304	SCV004039918	likely pathogenic	not provided	2024-07-22	criteria provided, single submitter	clinical testing	Identified in patients with DCM in published literature (PMID: 34137518, 35653365); 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: 34137518, 27694994, 22335739, 35653365)

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