Submissions for variant NM_001267550.2(TTN):c.102877A>G (p.Lys34293Glu)

gnomAD frequency: 0.00016  dbSNP: rs72629783

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172604	SCV000051278	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040925	SCV000064616	uncertain significance	not specified	2014-09-16	criteria provided, single submitter	clinical testing	The p.Lys31725Glu variant in TTN has been identified by our laboratory in 1 adul t with DCM and 1 child with complex cardiomyopathy, both of whom carry an additi onal likely pathogenic variant, as well as 1 adolescent with DCM. This variant h as also been identified in 20/66678 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72629783). Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Lys31725Glu variant is uncertain.
Eurofins Ntd Llc (ga)	RCV000172604	SCV000338012	uncertain significance	not provided	2015-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465722	SCV000542621	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000040925	SCV000597712	uncertain significance	not specified	2017-02-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000172604	SCV000615964	uncertain significance	not provided	2018-10-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000040925	SCV000728947	likely benign	not specified	2018-01-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769849	SCV000901275	uncertain significance	Cardiomyopathy	2016-05-02	criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293056	SCV001434038	likely benign	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Baylor Genetics	RCV001333490	SCV001526082	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2018-03-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002390175	SCV002672881	likely benign	Cardiovascular phenotype	2020-03-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040925	SCV003923259	likely benign	not specified	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: TTN c.95173A>G (p.Lys31725Glu) results in a conservative amino acid change located in the M-band of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 249004 control chromosomes, predominantly at a frequency of 0.00049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491304	SCV000298162	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2016-05-01	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172604	SCV001798196	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172604	SCV001962870	likely benign	not provided		no assertion criteria provided	clinical testing