Submissions for variant NM_001267550.2(TTN):c.95566C>T (p.Arg31856Cys)

gnomAD frequency: 0.00003  dbSNP: rs72648261

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185019	SCV000237810	uncertain significance	not specified	2013-11-18	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,DCM-CRDM panel(s).
Ambry Genetics	RCV000253091	SCV000319206	uncertain significance	Cardiovascular phenotype	2013-11-25	criteria provided, single submitter	clinical testing	The p.R29288C variant (also known as c.87862C>T) is located in coding exon 292 of the TTNgene. This alteration results from a C to T substitution at nucleotide position 87862. The arginine at codon 29288 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on data from the NHLBI Exome Sequencing Project (ESP), the T-allele has an overall frequency of approximately0.02% (2/12418), having been observed in0.05% (2/4040)of African American alleles, and not observed in 8378 European American alleles studied.This variant was not reported in population-based cohorts in the Database of Single Nucleotide Polymorphisms (dbSNP) or the 1000 Genomes Project. 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 analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002500563	SCV002814993	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	2021-08-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895220	SCV004715525	uncertain significance	TTN-related condition	2024-01-10	criteria provided, single submitter	clinical testing	The TTN c.95566C>T variant is predicted to result in the amino acid substitution p.Arg31856Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. A different nucleotide substitution affecting the same amino acid (p.Arg31856His) has been reported in an individual with dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). At this time, the clinical significance of the c.95566C>T (p.Arg31856Cys) variant is uncertain due to the absence of conclusive functional and genetic evidence.