Submissions for variant NM_001267550.2(TTN):c.59113C>T (p.Arg19705Cys)

gnomAD frequency: 0.00024  dbSNP: rs72646839

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040416	SCV000064107	uncertain significance	not specified	2019-12-20	criteria provided, single submitter	clinical testing	The p.Arg17137Cys variant in TTN has been identified by our laboratory in 1 African American individual with RCM and a dilated left atrium who also carried a pathogenic variant in another gene that most likely explained their disease. This variant has also been identified in 0.04% (15/35302) of Latino chromosomes by the gnomAD (https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg17137Cys variant is uncertain.
GeneDx	RCV000725816	SCV000237350	likely benign	not provided	2019-11-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30924900, 26567375)
Eurofins Ntd Llc (ga)	RCV000725816	SCV000339584	uncertain significance	not provided	2018-01-24	criteria provided, single submitter	clinical testing
Invitae	RCV000469250	SCV000542455	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-13	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852513	SCV000995209	uncertain significance	Long QT syndrome	2018-06-05	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000725816	SCV001475786	uncertain significance	not provided	2020-02-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040416	SCV002074509	likely benign	not specified	2022-01-31	criteria provided, single submitter	clinical testing	Variant summary: TTN c.51409C>T (p.Arg17137Cys) results in a non-conservative amino acid change located in the A-band region 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 0.00024 in 248286 control chromosomes, predominantly at a frequency of 0.00044 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.51409C>T has been reported in the literature in individuals affected with different Cardiomyopathies (Begay_2015, Klauke_2017). In a family reported by Klauke_2017, two sisters with arrhythmogenic right ventricular cardiomyopathy were genotyped; one sister carried this variant and the other sister carried the reference allele, showing the variant did not segregate with the disease phenotype. These siblings also carried other pathogenic variants (PLN c.40_42delAGA, p.Arg14del) which segregated with disease, providing supporting evidence for a benign role of TTN c.51409C>T. An undisclosed pathogenic co-occurence was also reported by ClinVar submitter "Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine" (Accession: SCV000064107.7). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002321523	SCV002609623	likely benign	Cardiovascular phenotype	2019-09-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491963	SCV000298155	likely benign	Arrhythmogenic right ventricular dysplasia 9	2016-05-01	no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725816	SCV001980481	likely benign	not provided		no assertion criteria provided	clinical testing