Submissions for variant NM_005120.3(MED12):c.1849A>G (p.Thr617Ala) (rs765417606)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000224083	SCV000250602	uncertain significance	not provided	2015-11-20	criteria provided, single submitter	clinical testing	p.Thr617Ala (ACT>GCT): c.1849 A>G in exon 13 of the MED12 gene (NM_005120.2) The T617A variant of unknown significant in the MED12 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The T617A variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T617A 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 protein structure/function. However, no missense mutations in nearby residues have been reported in association with LS or related disorders indicating that this region of the protein may be tolerant of change. 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
UCLA Clinical Genomics Center, UCLA	RCV000199251	SCV000255409	likely pathogenic	X-linked mental retardation with marfanoid habitus syndrome; FG syndrome 1; Ohdo syndrome, X-linked	2013-04-23	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000224083	SCV000281467	uncertain significance	not provided	2016-04-29	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Ambry Genetics	RCV000622207	SCV000739138	uncertain significance	Cardiovascular phenotype	2018-08-09	criteria provided, single submitter	clinical testing	The p.T617A variant (also known as c.1849A>G), located in coding exon 13 of the MED12 gene, results from an A to G substitution at nucleotide position 1849. The threonine at codon 617 is replaced by alanine, an amino acid with similar properties. This alteration was identified in an individual with autism, craniofacial dysmorphic features, and it was inherited from his mother (Lee H et al. JAMA, 2014 Nov;312:1880-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.