Submissions for variant NM_005120.3(MED12):c.2881C>T (p.Arg961Trp)

dbSNP: rs80338758

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001528259	SCV000250607	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate prevention of normal suppression of GLI3, resulting in enhanced SHH signaling pathway activation (Zhou et al., 2012); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17334363, 31536828, 20981778, 26350204, 28369444, 31623504, 31618753, 33710394, 23091001, 19938245)
Baylor Genetics	RCV000012276	SCV000807262	pathogenic	FG syndrome 1	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 5-year-old male with mitochondrial disease, developmental delay, hypogammaglobulinemia, GI dysmotility, hypotonia, scoliosis, strabismus, dysmorphisms, failure to thrive, dilated cardiomyopathy
Fulgent Genetics, Fulgent Genetics	RCV000763632	SCV000894500	pathogenic	X-linked intellectual disability with marfanoid habitus; FG syndrome 1; Blepharophimosis - intellectual disability syndrome, MKB type	2018-10-31	criteria provided, single submitter	clinical testing
Center for Statistical Genetics, Columbia University	RCV001261368	SCV001438278	pathogenic	Intellectual disability	2020-10-16	criteria provided, single submitter	research
Ambry Genetics	RCV004018614	SCV001445037	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-06-30	criteria provided, single submitter	clinical testing	The c.2881C>T (p.R961W) alteration is located in coding exon 21 of the MED12 gene. This alteration results from a C to T substitution at nucleotide position 2881, causing the arginine (R) at amino acid position 961 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the MED12 c.2881C>T alteration was not observed, with coverage at this position. The c.2881C>T (p.R961W) alteration has been reported in multiple unrelated males with neurodevelopmental disorders (Risheg, 2007; Graham, 2008; Clark, 2009; Lyons, 2009). The p.R961 amino acid is not conserved in available vertebrate species. Functional analyses demonstrated that the p.R961W alteration in patient-derived cells showed increased signaling and/or activation of downstream genes and this dysregulated signaling contributes to the phenotypes of patients with FG and Lujan syndromes (Zhou, 2012; Donnio, 2017). The in silico prediction for the p.R961W alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV001330015	SCV001521605	pathogenic	Blepharophimosis - intellectual disability syndrome, MKB type	2019-03-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 17334363, 19938245, 28369444, 20981778, 26350204, 23091001]
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764560	SCV001584353	pathogenic	FG syndrome	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 961 of the MED12 protein (p.Arg961Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Opitz-Kaveggia syndrome (PMID: 17334363, 18805826, 19938245). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11520). Invitae Evidence 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 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. Experimental studies have shown that this missense change affects MED12 function (PMID: 23091001). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001528259	SCV002017256	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000012276	SCV003918979	pathogenic	FG syndrome 1	2023-04-20	criteria provided, single submitter	research
OMIM	RCV000012276	SCV000032510	pathogenic	FG syndrome 1	2008-08-08	no assertion criteria provided	literature only
GeneReviews	RCV000012276	SCV000041142	not provided	FG syndrome 1		no assertion provided	literature only	Most common pathogenic variant in persons with FG syndrome type 1
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415294	SCV000492674	pathogenic	Corpus callosum, agenesis of; Imperforate anus; Global developmental delay; Abnormal facial shape; Broad thumb; Intellectual disability	2016-01-27	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528259	SCV001739682	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528259	SCV001952282	pathogenic	not provided		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV001330015	SCV005091317	likely pathogenic	Blepharophimosis - intellectual disability syndrome, MKB type	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team