Submissions for variant NM_030973.3(MED25):c.1438C>G (p.Leu480Val) (rs148214958)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197425	SCV000255139	uncertain significance	Charcot-Marie-Tooth disease, type 2	2018-05-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 480 of the MED25 protein (p.Leu480Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs148214958, ExAC 0.05%). This variant has not been reported in the literature in individuals with MED25-related disease. ClinVar contains an entry for this variant (Variation ID: 216779). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	RCV000756328	SCV000884103	uncertain significance	not provided	2017-09-05	criteria provided, single submitter	clinical testing	The p.Leu480Val variant (rs148214958) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 216779). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish European populations of 0.026% (identified in 33 out of 124,724 chromosomes). The leucine at codon 480 is highly conserved considering 11 species up to frog (Alamut software v2.9), although computational analyses return mixed results regarding the effect of this variant on MED25 protein structure/function (SIFT: damaging, PolyPhen2: benign, and Mutation Taster: disease causing). Thus, based on the available information, the clinical significance of the p.Leu480Val variant cannot be determined with certainty.
Fulgent Genetics,Fulgent Genetics	RCV000765458	SCV000896749	uncertain significance	Charcot-Marie-Tooth disease type 2B2; Basel-Vanagaite-Smirin-Yosef syndrome	2018-10-31	criteria provided, single submitter	clinical testing

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