Submissions for variant NM_001267550.2(TTN):c.415C>T (p.Arg139Trp)

gnomAD frequency: 0.00005  dbSNP: rs752970602

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185332	SCV000238217	uncertain significance	not provided	2017-12-13	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 variants 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). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000466012	SCV000542993	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-02-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620159	SCV000735152	uncertain significance	Cardiovascular phenotype	2018-04-04	criteria provided, single submitter	clinical testing	The p.R139W variant (also known as c.415C>T), located in coding exon 3 of the TTN gene, results from a C to T substitution at nucleotide position 415. The arginine at codon 139 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798657	SCV002042497	uncertain significance	Cardiomyopathy	2019-12-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824666	SCV002074483	uncertain significance	not specified	2022-01-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.415C>T (p.Arg139Trp) results in a non-conservative amino acid change located in the Z-disk band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251268 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8.4e-05 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.415C>T in individuals affected with Dilated 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 at our laboratory (MYH7 c.2722C>G, p.Leu908Val), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002485261	SCV002781357	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	2021-07-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000185332	SCV004148230	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000185332	SCV004225945	uncertain significance	not provided	2022-06-17	criteria provided, single submitter	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003387791	SCV004099329	uncertain significance	Hypertrophic cardiomyopathy 9	2023-10-30	no assertion criteria provided	clinical testing