ClinVar Genomic variation as it relates to human health
NM_001085049.3(MRAS):c.68G>T (p.Gly23Val)
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_001085049.3(MRAS):c.68G>T (p.Gly23Val)
Variation ID: 635781 Accession: VCV000635781.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q22.3 3: 138372951 (GRCh38) [ NCBI UCSC ] 3: 138091793 (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 Jul 15, 2019 Jun 24, 2023 Feb 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001085049.3:c.68G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001078518.1:p.Gly23Val missense NM_001252090.2:c.68G>T NP_001239019.1:p.Gly23Val missense NM_001252091.1:c.-35-24373G>T intron variant NM_001252092.2:c.-36+23919G>T intron variant NM_001252093.2:c.-36+24184G>T intron variant NM_012219.4:c.68G>T NP_036351.3:p.Gly23Val missense NC_000003.12:g.138372951G>T NC_000003.11:g.138091793G>T - Protein change
- G23V
- Other names
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- Canonical SPDI
- NC_000003.12:138372950:G: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
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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
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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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MRAS | - | - |
GRCh38 GRCh37 |
189 | 215 |
Conditions - Germline
Condition
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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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000787303.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 7, 2023 | RCV003155311.1 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Jun 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 11
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001522083.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 11
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841392.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 28289718). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000635781). A different missense change at the same codon (p.Gly23Arg) has been reported to be associated with MRAS related disorder (ClinVar ID: VCV000560681 / PMID: 31108500). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal facial shape (present) , Hydrocephalus (present) , Hypertrophic cardiomyopathy (present) , Short stature (present) , Intellectual disability (present)
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Pathogenic
(Feb 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844428.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: MRAS c.68G>T (p.Gly23Val) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. … (more)
Variant summary: MRAS c.68G>T (p.Gly23Val) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 208010 control chromosomes (gnomAD). c.68G>T has been reported in the literature as a de novo occurrence in an individual affected with Noonan Syndrome with Cardiac Hypertrophy (Higgins_2017). This suggests that the variant is likely associated with disease. Several publications report experimental evidence evaluating an impact on protein function and found that the variant results in a gain of function (e.g. Higgins_2017, Motta_2020). The variant causes an overactivation of the RAS/MAPK pathway with up to 40-fold more GTP loading than WT MRAS after stimulation with EGF, indicating that the variant protein is constituatively active (Higgins_2017). Additionally, the variant was found to elicit a cardiac hypertrophy phenotype in iPSC-derived cardiomyocytes that includes increased cell size, changes in cardiac gene expression, and abnormal calcium handling (Higgins_2019). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 11
Affected status: yes
Allele origin:
de novo
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Eurofins-Biomnis
Accession: SCV003935069.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
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Pathogenic
(Jul 11, 2019)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 11
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000926240.1
First in ClinVar: Jul 15, 2019 Last updated: Jul 15, 2019 |
Comment on evidence:
In a 15-year-old girl with Noonan syndrome-11 (NS11; 618499), Higgins et al. (2017) identified a heterozygous c.68G-T transversion (c.68G-T, NM_012219) in the MRAS gene resulting … (more)
In a 15-year-old girl with Noonan syndrome-11 (NS11; 618499), Higgins et al. (2017) identified a heterozygous c.68G-T transversion (c.68G-T, NM_012219) in the MRAS gene resulting in a glycine-to-valine substitution at codon 23 (G23V). This variant occurred as a de novo event and was not seen in over 280,000 alleles in gnomAD. In silico and structural analyses predicted that this variant would result in constitutive activation of the protein. Biochemical studies showed a 40-fold increase in GTP loading, as well as increased ERK activation and signaling and transcription activation in response to growth factors. Young et al. (2018) showed that the MRAS mutation G23V, equivalent to the oncogenic G13V in classical RAS proteins, showed increased interaction with other effectors such as BRAF (164757), CRAF (RAF1; 164760), and AF6 (MLLT4; 159559), consistent with activating mutations leading to GTP-loading of MRAS. (less)
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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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Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy. | Motta M | Human molecular genetics | 2020 | PMID: 31108500 |
MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene. | Higgins EM | Circulation. Genomic and precision medicine | 2019 | PMID: 31638832 |
SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. | Young LC | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 30348783 |
Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy. | Higgins EM | JCI insight | 2017 | PMID: 28289718 |
Text-mined citations for rs1576359216 ...
HelpRecord last updated Jun 24, 2023
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.