Submissions for variant NM_001267550.2(TTN):c.25481G>A (p.Arg8494Gln)

gnomAD frequency: 0.00058  dbSNP: rs201418615

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172687	SCV000055047	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000172687	SCV000232857	uncertain significance	not provided	2014-08-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215717	SCV000272603	uncertain significance	not specified	2015-07-29	criteria provided, single submitter	clinical testing	The p.Arg7250Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (15/9798) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs201418615). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Arg7250Gln variant is uncertain.
Invitae	RCV001083467	SCV000555448	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000172687	SCV000714643	likely benign	not provided	2020-10-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27604489, 23861362)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000215717	SCV001431968	likely benign	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: TTN c.21749G>A (p.Arg7250Gln) results in a conservative amino acid change located in the I-band domain 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 0.0002 in 280342 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 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. To our knowledge, no occurrence of c.21749G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000172687	SCV003824797	likely benign	not provided	2023-08-17	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172687	SCV001919643	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172687	SCV001966755	likely benign	not provided		no assertion criteria provided	clinical testing