Submissions for variant NM_001267550.2(TTN):c.55340C>T (p.Pro18447Leu)

gnomAD frequency: 0.00001  dbSNP: rs397517622

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040374	SCV000064065	uncertain significance	not specified	2011-12-23	criteria provided, single submitter	clinical testing	The Pro15879Leu variant (TTN) has not been previously reported nor previously id entified by our laboratory. Proline (Pro) at position 15879 is not conserved in some mammals, increasing the likelihood that a change would be tolerated. Comput ational predictions on the impact to the protein are mixed (AlignGVGD = inconclu sive, SIFT = pathogenic), though the accuracy of these tools is unknown. Additio nal information is needed to fully assess the clinical significance of the Pro15 879Leu variant.
GeneDx	RCV000040374	SCV000237313	uncertain significance	not specified	2014-03-28	criteria provided, single submitter	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040374	SCV002570989	uncertain significance	not specified	2023-01-09	criteria provided, single submitter	clinical testing	Variant summary: TTN c.47636C>T (p.Pro15879Leu) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 243424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.47636C>T has been reported in the literature in at least one individual affected with Cardiomyopathy. This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.