Submissions for variant NM_001267550.2(TTN):c.79546G>A (p.Gly26516Ser)

gnomAD frequency: 0.00016  dbSNP: rs776256093

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474513	SCV000542974	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000727779	SCV000730769	likely benign	not provided	2020-06-12	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727779	SCV000855173	uncertain significance	not provided	2018-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000603844	SCV001448540	uncertain significance	not specified	2020-11-17	criteria provided, single submitter	clinical testing	Variant summary: TTN c.71842G>A (p.Gly23948Ser) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 247684 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.71842G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727779	SCV001474375	uncertain significance	not provided	2020-07-24	criteria provided, single submitter	clinical testing	The TTN c.79546G>A, p.Gly26516Ser variant (rs776256093; ClinVar Variation ID: 405063) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Gly26516Ser variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.
Ambry Genetics	RCV002348269	SCV002646062	uncertain significance	Cardiovascular phenotype	2018-09-12	criteria provided, single submitter	clinical testing	The p.G17451S variant (also known as c.52351G>A), located in coding exon 153 of the TTN gene, results from a G to A substitution at nucleotide position 52351. The glycine at codon 17451 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000727779	SCV003821738	uncertain significance	not provided	2020-10-20	criteria provided, single submitter	clinical testing