X-71127367-C-T

Variant names:

• chrX-71127367-C-T
• rs80338758
• NM_005120.3:c.2881C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_005120.3(MED12):​c.2881C>T​(p.Arg961Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 5.85

Genes affected

MED12 (HGNC:11957): (mediator complex subunit 12) The initiation of transcription is controlled in part by a large protein assembly known as the preinitiation complex. A component of this preinitiation complex is a 1.2 MDa protein aggregate called Mediator. This Mediator component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates. The MED12 protein is essential for activating CDK8 kinase. Defects in this gene cause X-linked Opitz-Kaveggia syndrome, also known as FG syndrome, and Lujan-Fryns syndrome. [provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MED12 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 108 curated benign missense variants. Gene score misZ: 6.5797 (above the threshold of 3.09). GenCC associations: The gene is linked to MED12-related intellectual disability syndrome, X-linked intellectual disability with marfanoid habitus, blepharophimosis - intellectual disability syndrome, MKB type, FG syndrome 1, cholestasis-pigmentary retinopathy-cleft palate syndrome.
• PP5: Variant X-71127367-C-T is Pathogenic according to our data. Variant chrX-71127367-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71127367-C-T is described in Lovd as [Pathogenic]. Variant chrX-71127367-C-T is described in Lovd as [Pathogenic]. Variant chrX-71127367-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.2881C>T	p.Arg961Trp	missense_variant	Exon 21 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.2881C>T	p.Arg961Trp	missense_variant	Exon 21 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FG syndrome 1 Pathogenic:4 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Most common pathogenic variant in persons with FG syndrome type 1 -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

Aug 08, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 14, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.71 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011520 /PMID: 17334363). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 17334363). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Blepharophimosis - intellectual disability syndrome, MKB type Pathogenic:2

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Mar 12, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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] -

Imperforate anus;C0175754:Corpus callosum, agenesis of;C0424503:Abnormal facial shape;C0426891:Broad thumb;C0557874:Global developmental delay;C3714756:Intellectual disability Pathogenic:1

Jan 27, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jun 30, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

FG syndrome Pathogenic:1

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

X-linked intellectual disability with marfanoid habitus;C3698541:Blepharophimosis - intellectual disability syndrome, MKB type;C5399762:FG syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Pathogenic:1

Oct 16, 2020

Center for Statistical Genetics, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.1	.;L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.4	.;N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.55
MutPred		0.67		.;Loss of disorder (P = 0.015);Loss of disorder (P = 0.015);
MVP		0.96
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338758; hg19: chrX-70347217; COSMIC: COSV61343293; COSMIC: COSV61343293;