ClinVar Miner

Submissions for variant NM_005120.3(MED12):c.5922G>T (p.Gln1974His)

dbSNP: rs879255528
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002313968 SCV000739139 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-02-04 criteria provided, single submitter clinical testing The p.Q1974H variant (also known as c.5922G>T), located in coding exon 41 of the MED12 gene, results from a G to T substitution at nucleotide position 5922. The glutamine at codon 1974 is replaced by histidine, an amino acid with highly similar properties. In a family study, this variant was observed to co-segregate with another alteration in the OGT gene in three brothers with severe non-syndromic intellectual deficiency and mild dysmorphic features (Bouazzi H et al. Clin Case Rep. 2015;3(7):604-9). In the same study, this variant, but not the OGT alteration, was confirmed in their mother who was described to have language delays and no dysmorphic features. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6230 samples with coverage at this position. This amino acid position is well 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 variant remains unclear.
CeGaT Center for Human Genetics Tuebingen RCV000762650 SCV000892984 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
Invitae RCV003595901 SCV002184183 uncertain significance FG syndrome 2021-08-11 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MED12 protein function. ClinVar contains an entry for this variant (Variation ID: 252965). This missense change has been observed in individual(s) with non-syndromic intellectual disability (PMID: 26273451). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 1974 of the MED12 protein (p.Gln1974His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine.
GeneReviews RCV000239403 SCV000297774 not provided FG syndrome 1 no assertion provided literature only Reported in male sibs with nonspecific intellectual disability
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital RCV000515779 SCV000611864 benign Intellectual disability 2017-12-06 no assertion criteria provided clinical testing Variant inherited from healthy grandfather of index patient

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