Submissions for variant NM_001267550.2(TTN):c.71624C>A (p.Thr23875Asn)

gnomAD frequency: 0.00001  dbSNP: rs771783837

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184786	SCV000237497	uncertain significance	not specified	2013-09-30	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).
Mayo Clinic Laboratories, Mayo Clinic	RCV001508108	SCV001714038	uncertain significance	not provided	2020-10-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000184786	SCV002041799	uncertain significance	not specified	2021-11-22	criteria provided, single submitter	clinical testing	Variant summary: TTN c.63920C>A (p.Thr21307Asn) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 248464 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.63920C>A has been reported in the literature as NM_001267550:c.71624C>A (p.Thr23875Asn) in at-least one individual affected with Dilated Cardiomyopathy (example, Mazzarotto_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (Transthyretin Amyloidosis-TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002327004	SCV002632599	uncertain significance	Cardiovascular phenotype	2019-11-25	criteria provided, single submitter	clinical testing	The p.T14810N variant (also known as c.44429C>A), located in coding exon 153 of the TTN gene, results from a C to A substitution at nucleotide position 44429. The threonine at codon 14810 is replaced by asparagine, an amino acid with similar properties. This amino acid position is not well 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.
Fulgent Genetics, Fulgent Genetics	RCV002503734	SCV002816306	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	2021-09-06	criteria provided, single submitter	clinical testing