Submissions for variant NM_001267550.2(TTN):c.66977A>G (p.Lys22326Arg)

gnomAD frequency: 0.00189  dbSNP: rs202125813

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040515	SCV000064206	likely benign	not specified	2012-04-10	criteria provided, single submitter	clinical testing	Lys19758Arg in exon 266 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (12/3048) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). Lys19758Arg in exon 266 of TTN (allele frequenc y = 0.4%, 12/3048) **
GeneDx	RCV001703905	SCV000237447	likely benign	not provided	2020-09-18	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000040515	SCV000337566	likely benign	not specified	2015-11-12	criteria provided, single submitter	clinical testing
Invitae	RCV000464443	SCV000555261	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040515	SCV001476359	benign	not specified	2020-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040515	SCV002041816	benign	not specified	2021-11-29	criteria provided, single submitter	clinical testing	Variant summary: TTN c.59273A>G (p.Lys19758Arg) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 279656 control chromosomes, predominantly at a frequency of 0.0053 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13.5-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 African or African-American origin. c.59273A>G has been reported in the literature in an African American individual affected with Dilated Cardiomyopathy (Pugh_2014). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001839673	SCV002100372	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839674	SCV002100373	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839675	SCV002100374	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839672	SCV002100375	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371844	SCV002624578	likely benign	Cardiovascular phenotype	2018-11-14	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.
CeGaT Center for Human Genetics Tuebingen	RCV001703905	SCV004699126	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TTN: BP4, BS2
Clinical Genetics, Academic Medical Center	RCV000040515	SCV001924097	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001703905	SCV001958878	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001703905	SCV001964237	likely benign	not provided		no assertion criteria provided	clinical testing