VCV000225897.5 - ClinVar

NM_005120.3(MED12):c.1562G>A (p.Arg521His)

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.

(3)

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.

Uncertain significance

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.1562G>A (p.Arg521His)

Variation ID: 225897 Accession: VCV000225897.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71123171 (GRCh38) [ NCBI UCSC ] X: 70343021 (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	May 14, 2016	Oct 8, 2024	Jun 30, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_005120.3:c.1562G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005111.2:p.Arg521His	missense
NC_000023.11:g.71123171G>A
NC_000023.10:g.70343021G>A
NG_012808.1:g.9616G>A

Protein change

R521H

Other names

Canonical SPDI

NC_000023.11:71123170:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA10576140 dbSNP: rs875989806 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
LOC126863275	-	-	-	GRCh38	-	175

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	Uncertain significance (1)	criteria provided, single submitter	Jan 1, 2015	RCV000211106.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 30, 2020	RCV001753638.2
MED12-related disorder	Likely pathogenic (1)	no assertion criteria provided	Aug 12, 2024	RCV003985309.2

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.
Uncertain significance (Jan 01, 2015)	criteria provided, single submitter (Fieremans et al. (Hum Mutat 2016)) Method: literature only	not specified (Sporadic) Affected status: unknown Allele origin: de novo	Center for Human Genetics, University of Leuven Accession: SCV000268071.1 First in ClinVar: May 14, 2016 Last updated: May 14, 2016	Publications: PubMed (1) PubMed: 27159028 Number of individuals with the variant: 1 Clinical Features: Intellectual disability (present) , Autism (present) Family history: no Sex: female Geographic origin: Europe
Uncertain significance (Jun 30, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001987991.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more) Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27159028, 28369444, 26813965) (less)
Likely pathogenic (Aug 12, 2024)	no assertion criteria provided Method: clinical testing	MED12-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004796958.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The MED12 c.1562G>A variant is predicted to result in the amino acid substitution p.Arg521His. This variant has been reported as de novo in a female … (more) The MED12 c.1562G>A variant is predicted to result in the amino acid substitution p.Arg521His. This variant has been reported as de novo in a female with intellectual disability and significantly skewed X inactivation (Fieremans et al. 2016. PubMed ID: 27159028). This variant is reported in 0.013% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is classified as likely pathogenic. (less)

Comment:

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27159028, 28369444, 26813965)

Comment:

The MED12 c.1562G>A variant is predicted to result in the amino acid substitution p.Arg521His. This variant has been reported as de novo in a female with intellectual disability and significantly skewed X inactivation (Fieremans et al. 2016. PubMed ID: 27159028). This variant is reported in 0.013% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant 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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs875989806 ...

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.1562G>A (p.Arg521His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs875989806 ...