Submissions for variant NM_005120.3(MED12):c.1264C>T (p.Arg422Trp) (rs368913305)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000735096	SCV000250601	uncertain significance	not provided	2017-12-29	criteria provided, single submitter	clinical testing	p.Arg422Trp (R422W) CGG>TGG: c.1264 C>T in exon 9 of the MED12 gene (NM_005120.2) The R422W variant of unknown significance in the MED12 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It has been reported in the LOVD database as a variant of unknown signficance. It was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R422W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD,MACRO-BRAIN
Invitae	RCV000702451	SCV000831306	uncertain significance	FG syndrome	2018-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 422 of the MED12 protein (p.Arg422Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs368913305, ExAC 0.01%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with MED12-related disease. ClinVar contains an entry for this variant (Variation ID: 213632). 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: "Probably Damaging"; 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000735096	SCV000863291	uncertain significance	not provided	2018-09-06	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000766103	SCV000897582	uncertain significance	X-linked mental retardation with marfanoid habitus syndrome; FG syndrome; Ohdo syndrome, X-linked	2018-10-31	criteria provided, single submitter	clinical testing

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