Submissions for variant NM_005120.3(MED12):c.3884G>A (p.Arg1295His)

dbSNP: rs1556337063

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004822132	SCV000741910	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-11-01	criteria provided, single submitter	clinical testing	The c.3884G>A (p.R1295H) alteration is located in exon 28 (coding exon 28) of the MED12 gene. This alteration results from a G to A substitution at nucleotide position 3884, causing the arginine (R) at amino acid position 1295 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation, has been identified in individuals with features consistent with MED12-related disorder, and segregated with disease in at least one family (Donnio, 2017; Srivastava, 2019; Maia, 2023; Callier, 2013; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV001731816	SCV001983826	likely pathogenic	not provided	2021-05-03	criteria provided, single submitter	clinical testing	Segregated in an affected hemizygous brother in one family, and a heterozygous mother with moderate learning difficulties, skeletal and dysmorphic features, mitral valve prolapse, and skewed X-inactivation in another family (Callier et al., 2013; Donnio et al., 2017; Srivastava et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; A different missense change at this residue (R1295C) has been reported in the published literature in association with MED12-related disorders (Hu et al., 2016; Charzewska et al., 2018; Rubinato et al., 2019); This variant is associated with the following publications: (PMID: 31536828, 25644381, 33925166, 23506379, 28369444, 30729724)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003596074	SCV004268121	pathogenic	FG syndrome	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1295 of the MED12 protein (p.Arg1295His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked recessive MED12-related conditions (PMID: 23506379, 28369444, 30729724, 36271811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 521365). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MED12 function (PMID: 28369444). For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV001580316	SCV001809992	not provided	FG syndrome 1		no assertion provided	literature only	Reported in persons with nonspecific intellectual disability and features of Lujan syndrome and in male sibs with features of FG syndrome type 1 and Lujan syndrome