VCV002199055.6 - ClinVar

NM_005120.3(MED12):c.4022G>A (p.Arg1341Gln)

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.

(4)

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.4022G>A (p.Arg1341Gln)

Variation ID: 2199055 Accession: VCV002199055.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71130189 (GRCh38) [ NCBI UCSC ] X: 70350039 (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	Feb 8, 2023	Aug 11, 2024	May 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005120.3:c.4022G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005111.2:p.Arg1341Gln	missense
NM_005120.2:c.4022G>A
NC_000023.11:g.71130189G>A
NC_000023.10:g.70350039G>A
NG_012808.1:g.16634G>A

... more HGVS ... less HGVS

Protein change

R1341Q

Other names

Canonical SPDI

NC_000023.11:71130188: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.

Links

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.
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 10, 2023	RCV003443134.1
Blepharophimosis - intellectual disability syndrome, MKB type Cholestasis-pigmentary retinopathy-cleft palate syndrome FG syndrome 1 X-linked intellectual disability with marfanoid habitus	Uncertain significance (1)	criteria provided, single submitter	-	RCV003883207.1
FG syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 23, 2023	RCV003596217.2
Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (1)	criteria provided, single submitter	May 20, 2024	RCV004070837.2

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 (Apr 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004170329.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis … (more) Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function (less)
Uncertain significance (Aug 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: SCV003518358.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Comment: ClinVar contains an entry for this variant (Variation ID: 2199055). In summary, the available evidence is currently insufficient to determine the role of this variant … (more) ClinVar contains an entry for this variant (Variation ID: 2199055). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) performed at Invitae indicates that this missense variant is expected to disrupt MED12 protein function. This variant has not been reported in the literature in individuals affected with MED12-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1341 of the MED12 protein (p.Arg1341Gln). (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked intellectual disability with marfanoid habitus FG syndrome 1 Cholestasis-pigmentary retinopathy-cleft palate syndrome Blepharophimosis - intellectual disability syndrome, MKB type Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: maternal	Molecular Genetics Lab, CHRU Brest Accession: SCV004697734.1 First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024
Uncertain significance (May 20, 2024)	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: SCV003602218.3 First in ClinVar: Feb 07, 2023 Last updated: Aug 11, 2024	Comment: The c.4022G>A (p.R1341Q) alteration is located in exon 28 (coding exon 28) of the MED12 gene. This alteration results from a G to A substitution … (more) The c.4022G>A (p.R1341Q) alteration is located in exon 28 (coding exon 28) of the MED12 gene. This alteration results from a G to A substitution at nucleotide position 4022, causing the arginine (R) at amino acid position 1341 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/195918) total alleles studied. The highest observed frequency was 0.006% (1/17806) of South Asian alleles. This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)

Comment:

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function

Comment:

ClinVar contains an entry for this variant (Variation ID: 2199055). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) performed at Invitae indicates that this missense variant is expected to disrupt MED12 protein function. This variant has not been reported in the literature in individuals affected with MED12-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1341 of the MED12 protein (p.Arg1341Gln).

Comment:

The c.4022G>A (p.R1341Q) alteration is located in exon 28 (coding exon 28) of the MED12 gene. This alteration results from a G to A substitution at nucleotide position 4022, causing the arginine (R) at amino acid position 1341 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/195918) total alleles studied. The highest observed frequency was 0.006% (1/17806) of South Asian alleles. This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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 this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_005120.3(MED12):c.4022G>A (p.Arg1341Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...