Submissions for variant NM_005120.3(MED12):c.4147G>A (p.Ala1383Thr)

dbSNP: rs863223696

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195723	SCV000250593	pathogenic	not provided	2018-10-18	criteria provided, single submitter	clinical testing	The A1383T variant in the MED12 gene has been reported previously as a pathogenic variant in two male siblings with microcephaly, dysmorphic features, failure to thrive, developmental delay, increased muscle tone, and chordee (Langely et al., 2015). The A1383T variant was not observed in approximately 6200 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 A1383T 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A1383T as a pathogenic variant.
Ambry Genetics	RCV000622415	SCV000742505	uncertain significance	Inborn genetic diseases	2017-05-08	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV001808556	SCV002059580	uncertain significance	Blepharophimosis - intellectual disability syndrome, MKB type	2020-08-28	criteria provided, single submitter	clinical testing
3billion	RCV002051827	SCV002318677	uncertain significance	X-linked intellectual disability with marfanoid habitus	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MED12 related disorder (PMID:26338144). It is not observed in the gnomAD v2.1.1 dataset. A missense variant is a common mechanism. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Invitae	RCV003595886	SCV004299604	likely pathogenic	FG syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1383 of the MED12 protein (p.Ala1383Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MED12-related conditions (PMID: 26338144, 36271811). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 213624). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MED12 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneReviews	RCV000239402	SCV000297771	not provided	FG syndrome 1		no assertion provided	literature only	Reported in male sibs with nonspecific intellectual disability