Submissions for variant NM_001267550.2(TTN):c.47758A>C (p.Lys15920Gln)

gnomAD frequency: 0.00001  dbSNP: rs775513269

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517781	SCV000616093	uncertain significance	not specified	2016-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550143	SCV000643241	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with glutamine at codon 15920 of the TTN protein (p.Lys15920Gln). There is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs775513269, ExAC 0.2%). This variant has not been reported in the literature in individuals with TTN-related disease. This variant identified in the TTN gene is located in the A band of the resulting protein (PMID: 25589632). It is unclear how this variant impacts the function of this protein. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000617706	SCV000737266	uncertain significance	Cardiovascular phenotype	2017-06-16	criteria provided, single submitter	clinical testing	The p.K6855Q variant (also known as c.20563A>C), located in coding exon 81 of the TTN gene, results from an A to C substitution at nucleotide position 20563. The lysine at codon 6855 is replaced by glutamine, 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.
GeneDx	RCV000786258	SCV001825594	likely benign	not provided	2020-02-19	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786258	SCV000925009	uncertain significance	not provided	2018-02-05	no assertion criteria provided	provider interpretation	p.Lys15920Gln (c.47758A>C) in exon 254 of the TTN gene (NM_001267550.2) Chromosome location 2:179482054 T / G Based on the information reviewed below, including the lack of case data and its higher prevalence among individuals who share our patient's Latino ancestry, we classify this as a Variant of Uncertain Significance (VUS), probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. According to the Invitae report, this variant has not been reported in the literature in association with disease. Truncating (nonsense, frameshift, essential splice site) variants in TTN have been strongly implicated in dilated cardiomyopathy, whereas the impact of missense variants in this gene remains unclear. In general population samples, there is a high prevalence of rare or novel TTN missense variants, making it likely that testing anyone's TTN genes would uncover such a variant. Specifically, Herman et al. (2012) note that every study subject, including controls, had approximately 1 rare (MAF <1%) missense variant in TTN. As such, we generally consider these to be variants of uncertain significance, probably benign. According to the Invitae report, however, algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This prediction has not been confirmed by published transcriptional studies. This variant is found in the A-band of titin, and exon 254 is present in 100% of TTN transcripts (https://cardiodb.org/titin/). Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease. However, it is not clear that this specific variant actually alters protein splicing. The glutamine amino acid residue is found as the default amino acid in at least one mammalian species, suggesting that this missense change does not adversely affect protein function. Furthermore, this variant was reported in 9 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 9 out of 12,389 individuals with Latino ancestry (for the highest allele frequency: 0.036%), and no individuals with other ancestry. Ovarall minor allele frequency (MAF) = 0.005%. This raises the possibility that it is a benign, ethnicity-specific variant. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.