Submissions for variant NM_001267550.2(TTN):c.27914G>A (p.Arg9305Gln)

gnomAD frequency: 0.00001  dbSNP: rs397517527

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040073	SCV000063764	uncertain significance	not specified	2017-03-27	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Genetic Services Laboratory, University of Chicago	RCV000040073	SCV000597703	uncertain significance	not specified	2016-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV001087344	SCV000642917	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000730993	SCV000858763	uncertain significance	not provided	2017-12-21	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852884	SCV000995618	likely benign	Primary dilated cardiomyopathy	2018-07-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040073	SCV003801239	likely benign	not specified	2023-01-09	criteria provided, single submitter	clinical testing	Variant summary: TTN c.24182G>A (p.Arg8061Gln) results in a conservative amino acid change located in the I-band of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 245666 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3 fold of 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. To our knowledge, no occurrence of c.24182G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five 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 (VUS n=3, likely benign n=2). Based on the evidence outlined above, the variant was classified as likely benign.