Submissions for variant NM_005120.3(MED12):c.1996A>G (p.Met666Val)

gnomAD frequency: 0.00001  dbSNP: rs1401003961

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198284	SCV001369164	uncertain significance	X-linked intellectual disability with marfanoid habitus	2019-08-12	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in hemizygous state.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002071852	SCV002495838	uncertain significance	X-linked intellectual disability with marfanoid habitus; FG syndrome 1; Blepharophimosis - intellectual disability syndrome, MKB type	2022-01-19	criteria provided, single submitter	clinical testing	MED12 NM_005120.3 exon 14 p.Met666Val (c.1996A>G): This variant has not been reported in the literature but is present in 0.007% (1/13551) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/X-70344635-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:931587). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV002418659	SCV002720926	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-03-01	criteria provided, single submitter	clinical testing	The p.M666V variant (also known as c.1996A>G), located in coding exon 14 of the MED12 gene, results from an A to G substitution at nucleotide position 1996. The methionine at codon 666 is replaced by valine, an amino acid with highly similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.0006% (1/181286) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.007% (1/13551) of East Asian alleles. This amino acid position is highly 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 alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003770216	SCV002994522	likely benign	FG syndrome	2022-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003438719	SCV004165341	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing