Submissions for variant NM_001267550.2(TTN):c.106537A>G (p.Lys35513Glu)

gnomAD frequency: 0.00006  dbSNP: rs551063889

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000693169	SCV000821026	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 35513 of the TTN protein (p.Lys35513Glu). This variant is present in population databases (rs551063889, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 571911). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001564944	SCV001473925	uncertain significance	not provided	2020-01-28	criteria provided, single submitter	clinical testing	The TTN c.106537A>G; p.Lys35513Glu variant (rs551063889; ClinVar Variation ID: 571911) is rare in the general population (<1% 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.Lys35513Glu 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.
GeneDx	RCV001564944	SCV001788192	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Ambry Genetics	RCV002422506	SCV002676406	uncertain significance	Cardiovascular phenotype	2017-09-19	criteria provided, single submitter	clinical testing	The p.K26448E variant (also known as c.79342A>G), located in coding exon 187 of the TTN gene, results from an A to G substitution at nucleotide position 79342. The lysine at codon 26448 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other vertebrate species. Using the BDGP, ESEfinder and Human Splicing Finder (HSF) splice site prediction tools, this alteration is predicted to either abolish the native splice acceptor site, create a new acceptor splice site, or strengthen a cryptic acceptor splice site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). 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 variant remains unclear.
GenomeConnect, ClinGen	RCV002507203	SCV002817117	not provided	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Hypertrophic cardiomyopathy 9		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 09-15-2021 by Lab or GTR ID 506526. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Invitae Patient Insights Network	RCV004545883	SCV004228811	not provided	TTN-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-04-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.