ClinVar Genomic variation as it relates to human health
NM_005402.4(RALA):c.73G>A (p.Val25Met)
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
-
NM_005402.4(RALA):c.73G>A (p.Val25Met)
Variation ID: 521019 Accession: VCV000521019.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p14.1 7: 39686740 (GRCh38) [ NCBI UCSC ] 7: 39726339 (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 15, 2018 Jul 23, 2024 Jul 17, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005402.4:c.73G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005393.2:p.Val25Met missense NC_000007.14:g.39686740G>A NC_000007.13:g.39726339G>A - Protein change
- V25M
- Other names
- -
- Canonical SPDI
- NC_000007.14:39686739:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
---|---|---|---|---|---|---|
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. |
|||
RALA | - | - |
GRCh38 GRCh37 |
89 | 115 |
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. |
---|---|---|---|---|
Pathogenic (1) |
criteria provided, single submitter
|
Jul 18, 2019 | RCV000623667.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 6, 2022 | RCV000656548.8 | |
Pathogenic (2) |
criteria provided, single submitter
|
Jul 17, 2023 | RCV001380398.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV001526588.3 |
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
(Mar 29, 2019)
|
criteria provided, single submitter
Method: research
|
not provided
Affected status: yes
Allele origin:
de novo
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Accession: SCV000778580.2
First in ClinVar: Jun 30, 2018 Last updated: Apr 09, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Autistic behavior (present) , Abnormal facial shape (present) , Intellectual disability, moderate (present) , Microcephaly (present) , speech difficulties (present) , Clinodactyly of the 5th … (more)
Autistic behavior (present) , Abnormal facial shape (present) , Intellectual disability, moderate (present) , Microcephaly (present) , speech difficulties (present) , Clinodactyly of the 5th finger (present) (less)
|
|
Pathogenic
(Jul 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741416.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Asian/Caucasian/Hawaiian/Filipino
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Intellectual disability
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737016.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009676.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
Pathogenic
(Sep 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003460006.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RALA function (PMID: 30500825). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RALA function (PMID: 30500825). 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 RALA protein function. ClinVar contains an entry for this variant (Variation ID: 521019). This missense change has been observed in individual(s) with RALA-related conditions (PMID: 30500825, 30761613). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 25 of the RALA protein (p.Val25Met). (less)
|
|
Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hiatt-Neu-Cooper neurodevelopmental syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086609.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Hiatt-Neu-Cooper neurodevelopmental syndrome (MIM#619311). However, gain of function is also suspected (PMID: 30500825). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Val25Leu)) has been reported as pathogenic (ClinVar), and observed as de novo in monozygotic twins with profound intellectual disability, absent speech and an abnormal MRI (PMID: 30500825). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (LOVD, ClinVar), and observed in at least three de novo individuals with intellectual disability and speech delay (PMID: 30500825). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Pathogenic
(May 06, 2021)
|
no assertion criteria provided
Method: literature only
|
HIATT-NEU-COOPER NEURODEVELOPMENTAL SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001578462.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment on evidence:
In 3 unrelated patients (patients 1-3) with Hiatt-Neu-Cooper neurodevelopmental syndrome (HINCONS; 619311), Hiatt et al. (2018) identified a de novo heterozygous c.73G-A transition (c.73G-A, NM_005402.3) … (more)
In 3 unrelated patients (patients 1-3) with Hiatt-Neu-Cooper neurodevelopmental syndrome (HINCONS; 619311), Hiatt et al. (2018) identified a de novo heterozygous c.73G-A transition (c.73G-A, NM_005402.3) in the RALA gene, resulting in a val25-to-met (V25M) substitution at a conserved residue in the GTP/GDP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the mutation caused a dramatic reduction in GTPase activity and RALA effector binding compared to controls. In a Japanese girl with HINCONS, Okamoto et al. (2019) identified a de novo heterozygous missense V25M mutation in the RALA gene. The mutation was found by whole-exome sequencing; functional studies of the variant and studies of patient cells were not performed. (less)
|
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 |
---|---|---|---|---|
RALA mutation in a patient with autism spectrum disorder and Noonan syndrome-like phenotype. | Okamoto N | Congenital anomalies | 2019 | PMID: 30761613 |
De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay. | Hiatt SM | PLoS genetics | 2018 | PMID: 30500825 |
The Small GTPase RalA controls exocytosis of large dense core secretory granules by interacting with ARF6-dependent phospholipase D1. | Vitale N | The Journal of biological chemistry | 2005 | PMID: 15980073 |
Activation of RalA is critical for Ras-induced tumorigenesis of human cells. | Lim KH | Cancer cell | 2005 | PMID: 15950903 |
The guanine nucleotide-binding switch in three dimensions. | Vetter IR | Science (New York, N.Y.) | 2001 | PMID: 11701921 |
Text-mined citations for rs1554297905 ...
HelpRecord last updated Sep 29, 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.