Submissions for variant NM_015271.5(TRIM2):c.1094C>G (p.Thr365Ser) (rs146686472)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000512807	SCV000609150	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV000550100	SCV000654614	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2R	2018-04-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with serine at codon 338 of the TRIM2 protein (p.Thr338Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs146686472, ExAC 0.03%). This variant has not been reported in the literature in individuals with TRIM2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000512807	SCV000884722	uncertain significance	not provided	2018-01-22	criteria provided, single submitter	clinical testing	The TRIM2 c.1013C>G; p.Thr338Ser variant (rs146686472), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.04% (identified on 45 out of 126,416 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 444644). The threonine at position 338 is moderately conserved, considering 12 species, and computational analyses of the effects of the p.Thr338Ser variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Thr338Ser variant cannot be determined with certainty.

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