ClinVar Miner

Submissions for variant NM_005120.3(MED12):c.887G>A (p.Arg296Gln)

dbSNP: rs1556334519
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623246 SCV000742996 likely pathogenic Inborn genetic diseases 2017-10-18 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV001805226 SCV002053925 likely pathogenic Blepharophimosis - intellectual disability syndrome, MKB type criteria provided, single submitter research
GeneDx RCV003117433 SCV003798803 pathogenic not provided 2022-08-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20301719, 28794916, 31536828, 34573309, 27500536, 27620904, 32682435)
3billion RCV001580299 SCV003841319 likely pathogenic FG syndrome 1 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000522111). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University RCV001805226 SCV004041613 likely pathogenic Blepharophimosis - intellectual disability syndrome, MKB type 2023-10-02 criteria provided, single submitter clinical testing This missense variant is absent from controls (PM2), and mRNA level analysis showed splicing variant causing 14 aminoacids inframe deletion in LCEWAV domain (NM_005120.3:r.847_888del ) (PM4) at the same time of missense effect p.Arg296Gln. This variant was cosegregated with both affected brothers and carrier mother (PP1), and symptoms were consistent with X-linked Ohdo syndrome (PP4). Multiple lines of computational evidence support a deleterious effect as CADD phred score is 31 (PP3), also previously reported as likely-pathogenic in ClinVae (PP5). This variant It is judged to be likely-pathogenic according to ACMG Guidelines, 2015.
Invitae RCV003596075 SCV004299603 pathogenic FG syndrome 2023-07-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt MED12 protein function. ClinVar contains an entry for this variant (Variation ID: 522111). This missense change has been observed in individual(s) with MED12 X-linked recessive associated conditions (PMID: 27500536, 28794916, 34573309). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 296 of the MED12 protein (p.Arg296Gln).
GeneReviews RCV001580299 SCV001809974 not provided FG syndrome 1 no assertion provided literature only Reported in persons with X-linked Ohdo syndrome and nonspecific intellectual disability

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