ClinVar Genomic variation as it relates to human health
NM_001664.4(RHOA):c.139G>A (p.Glu47Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001664.4(RHOA):c.139G>A (p.Glu47Lys)
Variation ID: 695069 Accession: VCV000695069.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 49375451 (GRCh38) [ NCBI UCSC ] 3: 49412884 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 6, 2020 Apr 15, 2024 Oct 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001664.4:c.139G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001655.1:p.Glu47Lys missense NM_001313941.2:c.139G>A NP_001300870.1:p.Glu47Lys missense NM_001313943.2:c.139G>A NP_001300872.1:p.Glu47Lys missense NM_001313944.2:c.129+10G>A intron variant NM_001313945.2:c.-105G>A 5 prime UTR NM_001313946.2:c.139G>A NP_001300875.1:p.Glu47Lys missense NM_001313947.2:c.139G>A NP_001300876.1:p.Glu47Lys missense NC_000003.12:g.49375451C>T NC_000003.11:g.49412884C>T NG_051308.1:g.41647G>A LRG_1085:g.41647G>A LRG_1085t1:c.139G>A LRG_1085p1:p.Glu47Lys - Protein change
- E47K
- Other names
- p.(Glu47Lys)
- Canonical SPDI
- NC_000003.12:49375450:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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RHOA | - | - |
GRCh38 GRCh37 |
16 | 28 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2019 | RCV001095368.10 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 6, 2022 | RCV001526531.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 5, 2023 | RCV001539108.12 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001526536.9 |
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. |
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Pathogenic
(Nov 28, 2019)
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criteria provided, single submitter
Method: research
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neuro-ectodermal phenotype
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Goettingen
Accession: SCV000999252.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Number of individuals with the variant: 4
Age: 3-35 years
Sex: female
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies
Affected status: yes
Allele origin:
somatic
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001736953.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hemihypertrophy
Affected status: yes
Allele origin:
somatic
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001736958.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(Nov 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001756849.2
First in ClinVar: Jul 24, 2021 Last updated: Dec 11, 2022 |
Comment:
Identified in multiple unrelated patients as a somatic mosaic variant in skin tissue with hypopigmented areas of the skin, dental anomalies, body asymmetry, hemihypotrophy and … (more)
Identified in multiple unrelated patients as a somatic mosaic variant in skin tissue with hypopigmented areas of the skin, dental anomalies, body asymmetry, hemihypotrophy and brain magnetic resonance imaging (MRI) anomalies in published literature (Vabres et al., 2019; Yigit et al., 2019); Published functional studies demonstrate a inactivating effect of the Glu47Lys RHOA variant (Vabres et al., 2019); 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; This variant is associated with the following publications: (PMID: 31570889, 31821646, 32335911) (less)
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Pathogenic
(Nov 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003836018.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Oct 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004629390.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 47 of the RHOA protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 47 of the RHOA protein (p.Glu47Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RHOA-related conditions (PMID: 31570889, 31821646). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 695069). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RHOA function (PMID: 31570889). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 29, 2020)
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no assertion criteria provided
Method: literature only
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ECTODERMAL DYSPLASIA WITH FACIAL DYSMORPHISM AND ACRAL, OCULAR, AND BRAIN ANOMALIES, SOMATIC MOSAIC
Affected status: not provided
Allele origin:
somatic
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OMIM
Accession: SCV001134930.2
First in ClinVar: Jan 06, 2020 Last updated: Feb 03, 2020 |
Comment on evidence:
In 5 unrelated patients (S1, S2, S4, S5, and S7) with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB; 618727), Vabres … (more)
In 5 unrelated patients (S1, S2, S4, S5, and S7) with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB; 618727), Vabres et al. (2019) identified somatic mosaicism for a c.139G-A transition (c.139G-A, NM_001664.3) in the RHOA gene, resulting in a glu47-to-lys (E47K) substitution at a highly conserved residue. The mutation was absent from blood samples of the patients, but in skin-derived DNA samples, mutant allele fractions ranged from 1.9% to 33.5%. The variant was not found in in-house WES data from approximately 1,500 individuals, or in the dbSNP (build 147), COSMIC, ExAC, or gnomAD databases. Immunocytochemical analysis of transfected NIH/3T3 cells displayed reduced cell spreading and a decreased number of stress fibers, as well as microtubule disorganization, indicating a dominant-negative or otherwise inactivating effect with the E47K variant. In addition, immunoblot analysis revealed reduced levels of MYPT1 (PPP1R12A; 602021) and MLC2 (MYL2; 160781) phosphorylation at sites targeted by a major downstream effector of activated RHOA. (less)
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Pathogenic
(Feb 14, 2023)
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no assertion criteria provided
Method: clinical testing
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Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies
(Somatic mutation)
Affected status: yes
Allele origin:
de novo
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV004812028.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
Clinical Features:
Premature birth (present) , Abnormal delivery (present) , Abdominal distention (present) , Maternal hypertension (present) , Congenital atresia of colon (present) , Caesarian section (present) … (more)
Premature birth (present) , Abnormal delivery (present) , Abdominal distention (present) , Maternal hypertension (present) , Congenital atresia of colon (present) , Caesarian section (present) , Abnormality of the dentition (present) , Facial asymmetry (present) , Prelingual sensorineural hearing impairment (present) , Sensorineural hearing loss disorder (present) , Astigmatism (present) , Cataract (present) , Retinal dystrophy (present) , Exotropia (present) , Depression (present) , Autism (present) , Brachydactyly (present) , Premature birth (present) , Abnormal cerebral white matter morphology (present) , Abnormality of primary teeth (present) , Polydactyly (present) , Abnormality of the scalp hair (present) , Hemiatrophy (present) (less)
Age: 10-19 years
Sex: female
Tissue: Blood
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype. | Yigit G | Human mutation | 2020 | PMID: 31821646 |
Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome. | Vabres P | Nature genetics | 2019 | PMID: 31570889 |
Text-mined citations for rs1575653629 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.