Submissions for variant NM_001267550.2(TTN):c.47513G>A (p.Arg15838Gln)

gnomAD frequency: 0.00026  dbSNP: rs199640194

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724914	SCV000237215	likely benign	not provided	2020-10-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213221	SCV000272657	uncertain significance	not specified	2015-10-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg13270Gln v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 32/66627 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199640194). Argin ine (Arg) at position 39809 is not conserved in evolutionarily distant species a nd 5 different reptile species carry a Glutamine (Gln), raising the possibility that this change may be tolerated. Additional computational prediction tools sug gest that the p.Arg13270Gln variant may not impact the protein, though this info rmation is not predictive enough to rule out pathogenicity. In summary, while th e clinical significance of the p.Arg13270Gln variant is uncertain, these data su ggest that it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000724914	SCV000332387	uncertain significance	not provided	2015-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV000459255	SCV000543061	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000213221	SCV000605483	uncertain significance	not specified	2016-12-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001332831	SCV001525258	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2019-12-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Athena Diagnostics	RCV000724914	SCV001880272	uncertain significance	not provided	2020-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415758	SCV002719634	likely benign	Cardiovascular phenotype	2020-07-24	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	RCV000213221	SCV003801234	likely benign	not specified	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.39809G>A (p.Arg13270Gln) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 247874 control chromosomes, predominantly at a frequency of 0.0005 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to 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 Non-Finnish European origin. To our knowledge, no occurrence of c.39809G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported via internal testing (MYBPC3 c.2374T>C, p.W792R), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as VUS (n=6) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000724914	SCV003822334	uncertain significance	not provided	2023-09-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486728	SCV004239920	benign	Cardiomyopathy	2022-07-08	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000724914	SCV002034592	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724914	SCV002037517	likely benign	not provided		no assertion criteria provided	clinical testing