Submissions for variant NM_001267550.2(TTN):c.57847+5_57847+8del

dbSNP: rs587782988

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498646	SCV000589934	uncertain significance	not provided	2019-08-06	criteria provided, single submitter	clinical testing	Reported in an individual with DCM (Dal Ferro et al., 2017); Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 155850; Landrum et al., 2016); Occurs within the consensus splice donor site; in silico analysis, including splice predictors and evolutionary conservation, suggests this variant damages the splice donor site of intron 245 and predicts it will cause abnormal gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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); This variant is associated with the following publications: (PMID: 28416588)
Invitae	RCV000642698	SCV000764385	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 295 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. It affects a nucleotide within the consensus splice site. 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 variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 28416588). ClinVar contains an entry for this variant (Variation ID: 155850). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 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.
Ambry Genetics	RCV003162598	SCV003860964	uncertain significance	Cardiovascular phenotype	2023-02-22	criteria provided, single submitter	clinical testing	The c.30652+5_30652+8delGTAA intronic variant, located in intron 122 of the TTN gene, results from a deletion of 4 nucleotides within intron 122 of the TTN gene. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Dal Ferro M et al. Heart, 2017 Nov;103:1704-1710). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486663	SCV004239966	uncertain significance	Cardiomyopathy	2023-03-17	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000143973	SCV000188854	uncertain significance	Primary dilated cardiomyopathy	2014-01-29	no assertion criteria provided	clinical testing