Submissions for variant NM_001267550.2(TTN):c.55745C>T (p.Pro18582Leu)

gnomAD frequency: 0.00011  dbSNP: rs201194435

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040378	SCV000064069	uncertain significance	not specified	2012-11-20	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Pro16014Leu var iant in TTN has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 2/8184 European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/; dbSNP rs201194435). Proline (Pro) at position 16014 is not conserved in mammals, as rat carries a leucine (Leu; this variant) at thi s position. Additional computational analyses (biochemical amino acid properties , AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the p rotein, though this information is not predictive enough to rule out pathogenici ty. Additional information is needed to fully assess the clinical significance o f this variant.
GeneDx	RCV000040378	SCV000237320	uncertain significance	not specified	2016-09-12	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).
Eurofins Ntd Llc (ga)	RCV000726466	SCV000344901	uncertain significance	not provided	2016-08-31	criteria provided, single submitter	clinical testing
Invitae	RCV000560126	SCV000643385	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-05-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726466	SCV001152866	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798162	SCV002042544	uncertain significance	Cardiomyopathy	2019-09-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726466	SCV003827211	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398609	SCV004103453	uncertain significance	TTN-related condition	2023-03-09	criteria provided, single submitter	clinical testing	The TTN c.55745C>T variant is predicted to result in the amino acid substitution p.Pro18582Leu. This variant has been reported in an individual with dilated cardiomyopathy (Table S5, PAtient DCM-06, Klauke et al. 2017. PubMed ID: 29253866). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179465886-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491099	SCV000298110	uncertain significance	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	clinical testing