Submissions for variant NM_001267550.2(TTN):c.87010G>A (p.Gly29004Ser)

gnomAD frequency: 0.00005  dbSNP: rs761251825

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184915	SCV000237675	uncertain significance	not specified	2015-08-24	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 panel(s).
Invitae	RCV000525673	SCV000643826	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with serine at codon 29004 of the TTN protein (p.Gly29004Ser). There is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs761251825, ExAC 0.01%). This variant has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 202937). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene 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, this variant has uncertain impact on TTN function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508465	SCV001714626	uncertain significance	not provided	2019-10-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354511	SCV002659692	uncertain significance	Cardiovascular phenotype	2018-09-24	criteria provided, single submitter	clinical testing	The p.G19939S variant (also known as c.59815G>A), located in coding exon 154 of the TTN gene, results from a G to A substitution at nucleotide position 59815. The glycine at codon 19939 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other 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.
Fulgent Genetics, Fulgent Genetics	RCV002485251	SCV002790044	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-10-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001508465	SCV003821693	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing