Submissions for variant NM_001267550.2(TTN):c.92451G>T (p.Glu30817Asp)

gnomAD frequency: 0.00005  dbSNP: rs397517755

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040793	SCV000064484	uncertain significance	not specified	2012-03-16	criteria provided, single submitter	clinical testing	The Glu28249Asp variant (TTN) has not been reported in the literature nor previo usly identified by our laboratory. Glutamic acid (Glu) at position 28249 is con served in evolution, suggesting that a change may impact the protein. Other com putational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, an d SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of th e Glu28249Asp variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226810	SCV000286913	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-08-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001698952	SCV000730668	likely benign	not provided	2021-05-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040793	SCV002572247	uncertain significance	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: TTN c.84747G>T (p.Glu28249Asp) results in a conservative amino acid change located in the A band domain of the encoded protein sequence. Three of four 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 248686 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.84747G>T has been reported in a cohort of non-compaction cardiomyopathy patients and authors classified the variant as VUS (example: van Waning_2018). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign, and as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance
Ambry Genetics	RCV002362646	SCV002660156	uncertain significance	Cardiovascular phenotype	2019-06-10	criteria provided, single submitter	clinical testing	The p.E21752D variant (also known as c.65256G>T), located in coding exon 166 of the TTN gene, results from a G to T substitution at nucleotide position 65256. The glutamic acid at codon 21752 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly 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.
Revvity Omics, Revvity	RCV001698952	SCV003827219	uncertain significance	not provided	2020-07-27	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001698952	SCV001923703	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001698952	SCV001966045	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001698952	SCV001979642	uncertain significance	not provided		no assertion criteria provided	clinical testing