VCV000134636.36 - ClinVar

NM_005120.3(MED12):c.4111C>T (p.Pro1371Ser)

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.

(10)

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.

Likely benign

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.4111C>T (p.Pro1371Ser)

Variation ID: 134636 Accession: VCV000134636.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71131613 (GRCh38) [ NCBI UCSC ] X: 70351463 (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	Jun 9, 2014	Oct 20, 2024	Dec 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005120.3:c.4111C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005111.2:p.Pro1371Ser	missense
NC_000023.11:g.71131613C>T
NC_000023.10:g.70351463C>T
NG_012808.1:g.18058C>T

Protein change

P1371S

Other names

Canonical SPDI

NC_000023.11:71131612: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.

0.00026 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00011

Exome Aggregation Consortium (ExAC) 0.00012

The Genome Aggregation Database (gnomAD) 0.00018

1000 Genomes Project 30x 0.00021

1000 Genomes Project 0.00026

Links

ClinGen: CA160389 dbSNP: rs587778437 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	1696	1938

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.
not specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000121329.4
FG syndrome 1	not provided (1)	criteria provided, single submitter	-	RCV000228384.12
not provided	Likely benign (4)	criteria provided, multiple submitters, no conflicts	May 1, 2022	RCV001697144.20
Familial thoracic aortic aneurysm and aortic dissection	Likely benign (1)	criteria provided, single submitter	Aug 25, 2022	RCV002321600.3
Blepharophimosis - intellectual disability syndrome, MKB type Cholestasis-pigmentary retinopathy-cleft palate syndrome FG syndrome 1 X-linked intellectual disability with marfanoid habitus	Likely benign (1)	criteria provided, single submitter	Dec 20, 2021	RCV002492431.2
FG syndrome	Likely benign (1)	criteria provided, single submitter	Dec 23, 2023	RCV003595865.2
MED12-related disorder	Likely benign (1)	no assertion criteria provided	Jul 15, 2022	RCV003985274.2

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.
Likely benign (Dec 23, 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: SCV000288800.8 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024
Likely benign (Jun 23, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000725242.2 First in ClinVar: Apr 09, 2018 Last updated: Sep 25, 2021	Comment: This variant is associated with the following publications: (PMID: 30006928)
Likely benign (May 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002546180.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: MED12: PP2, BP4, BS1 Number of individuals with the variant: 1
Likely benign (Dec 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Blepharophimosis - intellectual disability syndrome, MKB type Cholestasis-pigmentary retinopathy-cleft palate syndrome FG syndrome 1 X-linked intellectual disability with marfanoid habitus Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002801057.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Aug 25, 2022)	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: SCV002627101.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 24728327‚ 30006928‚ 33244166 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jul 15, 2022)	no assertion criteria provided Method: clinical testing	MED12-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004758661.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	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: SCV001953823.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001966193.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: literature only	FG syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001809996.2 First in ClinVar: Aug 27, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301719‚ 30006928 BookShelf: NBK1676 BookShelf: NBK1676 Comment: Reported in a male with nonspecific intellectual disability
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085502.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.	Li D	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33244166
The power of the Mediator complex-Expanding the genetic architecture and phenotypic spectrum of MED12-related disorders.	Charzewska A	Clinical genetics	2018	PMID: 30006928
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327

Text-mined citations for rs587778437 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_005120.3(MED12):c.4111C>T (p.Pro1371Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778437 ...