Submissions for variant NM_001267550.2(TTN):c.15495A>C (p.Lys5165Asn)

gnomAD frequency: 0.00001  dbSNP: rs794729608

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185331	SCV000238216	uncertain significance	not specified	2014-10-09	criteria provided, single submitter	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM-CRDM panel(s).
Ambry Genetics	RCV000251847	SCV000318951	uncertain significance	Cardiovascular phenotype	2013-09-12	criteria provided, single submitter	clinical testing	The p.K3921N variant (also known as c.11763A>C) is the 2nd to last nucleotide located in coding exon 48 of the TTNgene. This alteration results from an A to C substitution at nucleotide position 11763. The lysine at codon 3921 is replaced by asparagine, an amino acid with a few similar properties. ​This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not observed in 5982 samples (11964 alleles) with coverage at this position. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species.In addition, this alteration is predicted to be probably damaging by PolyPhen in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185331	SCV001362765	uncertain significance	not specified	2021-10-02	criteria provided, single submitter	clinical testing	Variant summary: TTN c.11763A>C (p.Lys3921Asn) results in a non-conservative amino acid change located in the I-Band of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant is also located within the putative exonic splice region as the second last nucleotide of exon 49 close to the canonical splice donor site. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.5e-06 in 234768 control chromosomes. 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.11763A>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant(s) has been observed in a specimen undergoing evaluation for familial cardiomyopathy at our laboratory (LMNA c.646C>T, p.Arg216Cys), providing supporting evidence for a benign role. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.