Submissions for variant NM_001267550.2(TTN):c.80209T>A (p.Cys26737Ser)

gnomAD frequency: 0.00001  dbSNP: rs566764105

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619393	SCV000735604	uncertain significance	Cardiovascular phenotype	2016-11-04	criteria provided, single submitter	clinical testing	The p.C17672S variant (also known as c.53014T>A), located in coding exon 153 of the TTN gene, results from a T to A substitution at nucleotide position 53014. The cysteine at codon 17672 is replaced by serine, an amino acid with dissimilar properties, and is located in the A-band region of the N2-B isoform of the titin protein. This variant was previously reported in the SNPDatabase as rs566764105. Based on data from gnomAD, the A allele has an overall frequency of less than 0.01% (7/281896) total alleles studied. The highest observed frequency was 0.037% (7/18872) of East Asian alleles. 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.
GeneDx	RCV000839813	SCV000981720	likely benign	not provided	2018-06-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235309	SCV003934167	uncertain significance	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.72505T>A (p.Cys24169Ser) results in a non-conservative amino acid change located in the A band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248610 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.72505T>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (examples: Liu_2017 and Yeh_2019). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 28256248, 31879508). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign, and as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.