VCV000011520.31 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 11520 Accession: VCV000011520.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71127367 (GRCh38) [ NCBI UCSC ] X: 70347217 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 26, 2024	Oct 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005120.3:c.2881C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005111.2:p.Arg961Trp	missense
NC_000023.11:g.71127367C>T
NC_000023.10:g.70347217C>T
NG_012808.1:g.13812C>T
	Q93074:p.Arg961Trp

... more HGVS ... less HGVS

Protein change

R961W

Other names

Canonical SPDI

NC_000023.11:71127366:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA324786 UniProtKB: Q93074#VAR_033112 OMIM: 300188.0001 dbSNP: rs80338758 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MED12		No evidence available	No evidence available	GRCh38 GRCh37	1707	1949

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
FG syndrome 1	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 20, 2023	RCV000012276.34
Abnormal facial shape Broad thumb Corpus callosum, agenesis of Global developmental delay Imperforate anus Intellectual disability	Pathogenic (1)	no assertion criteria provided	Jan 27, 2016	RCV000415294.4
Blepharophimosis - intellectual disability syndrome, MKB type FG syndrome 1 X-linked intellectual disability with marfanoid habitus	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763632.4
Blepharophimosis - intellectual disability syndrome, MKB type	Pathogenic (2)	criteria provided, single submitter	Mar 12, 2019	RCV001330015.4
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 6, 2022	RCV001528259.12
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Oct 16, 2020	RCV001261368.3
FG syndrome	Pathogenic (1)	criteria provided, single submitter	Oct 29, 2023	RCV003764560.2
Familial thoracic aortic aneurysm and aortic dissection	Likely pathogenic (1)	criteria provided, single submitter	Jun 30, 2020	RCV004018614.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Blepharophimosis - intellectual disability syndrome, MKB type FG syndrome 1 X-linked intellectual disability with marfanoid habitus Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894500.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Mar 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Blepharophimosis - intellectual disability syndrome, MKB type Affected status: yes Allele origin: maternal	Baylor Genetics Accession: SCV001521605.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (6) PubMed: 17334363‚ 19938245‚ 28369444‚ 20981778‚ 26350204‚ 23091001 Comment: 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, … (more) 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] (less)
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FG syndrome 1 (X-linked inheritance) Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV000807262.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022	Publications: PubMed (4) PubMed: 25326635‚ 17334363‚ 19938245‚ 20981778 Comment: 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 … (more) 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 (less)
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	FG syndrome 1 Affected status: yes Allele origin: maternal	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003918979.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023
Pathogenic (Oct 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Intellectual disability Affected status: yes Allele origin: inherited	Center for Statistical Genetics, Columbia University Accession: SCV001438278.1 First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020
Pathogenic (May 06, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000250607.5 First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Dec 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017256.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	FG syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001584353.3 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 17334363‚ 18805826‚ 19938245‚ 23091001 Comment: 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 … (more) 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). 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. Experimental studies have shown that this missense change affects MED12 function (PMID: 23091001). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jun 30, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001445037.4 First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 10405444‚ 17334363‚ 18805826‚ 18973276‚ 19938245‚ 23091001‚ 28369444 Comment: 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 … (more) 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. (less)
Pathogenic (Aug 08, 2008)	no assertion criteria provided Method: literature only	OPITZ-KAVEGGIA SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032510.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 17334363‚ 18691967 Comment on evidence: In the original family with what was designated the FG syndrome (305450) after the family initials, Risheg et al. (2007) found a 2881C-T transition in … (more) In the original family with what was designated the FG syndrome (305450) after the family initials, Risheg et al. (2007) found a 2881C-T transition in exon 21 of the MED12 gene that caused an arg961-to-trp amino acid substitution (R961W). They also found the same mutation in 5 other families. Failure to find the change in 451 normal men and in 343 consecutive newborn males suggested that it is not a rare polymorphic variant. The finding of the mutation in patients of various ethnic backgrounds suggested that families did not share a common ancestor. Ding et al. (2008) showed that both the R961W mutation associated with Opitz-Kaveggia syndrome and the MED12 asn1007-to-ser (N1007S; 300188.0002) mutation associated with Lujan-Fryns syndrome (309520) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST (600571) target genes. The authors noted that these mutations do not alter the ability of MED12 to support beta-catenin (see CTNNB1; 116806) transactivation. (less)
Pathogenic (Jan 27, 2016)	no assertion criteria provided Method: clinical testing	Abnormal facial shape Corpus callosum, agenesis of Imperforate anus Broad thumb Global developmental delay Intellectual disability Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492674.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952282.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739682.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Blepharophimosis - intellectual disability syndrome, MKB type Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091317.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
not provided (-)	no classification provided Method: literature only	FG syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000041142.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 20301719‚ 17334363‚ 19938245 BookShelf: NBK1676 BookShelf: NBK1676 Comment: Most common pathogenic variant in persons with FG syndrome type 1
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Comment:

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

Comment:

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)

Comment:

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). 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. Experimental studies have shown that this missense change affects MED12 function (PMID: 23091001). For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
MED12-Related Disorders.	Adam MP	-	2021	PMID: 20301719
MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.	Donnio LM	Human molecular genetics	2017	PMID: 28369444
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.	Grozeva D	Human mutation	2015	PMID: 26350204
MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling.	Zhou H	Proceedings of the National Academy of Sciences of the United States of America	2012	PMID: 23091001
Behavioral features in young adults with FG syndrome (Opitz-Kaveggia syndrome).	Graham JM Jr	American journal of medical genetics. Part C, Seminars in medical genetics	2010	PMID: 20981778
FG syndrome, an X-linked multiple congenital anomaly syndrome: the clinical phenotype and an algorithm for diagnostic testing.	Clark RD	Genetics in medicine : official journal of the American College of Medical Genetics	2009	PMID: 19938245
Clinical experience in the evaluation of 30 patients with a prior diagnosis of FG syndrome.	Lyons MJ	Journal of medical genetics	2009	PMID: 18805826
Behavior of 10 patients with FG syndrome (Opitz-Kaveggia syndrome) and the p.R961W mutation in the MED12 gene.	Graham JM Jr	American journal of medical genetics. Part A	2008	PMID: 18973276
Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation.	Ding N	Molecular cell	2008	PMID: 18691967
A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.	Risheg H	Nature genetics	2007	PMID: 17334363
Clinical and behavioral characteristics in FG syndrome.	Graham JM Jr	American journal of medical genetics	1999	PMID: 10405444
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Text-mined citations for rs80338758 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338758 ...