The M90I variant in the RIT1 gene has been reported previously in a Noonan syndrome cohort as a de novo change in an individual with hypertrophic cardiomyopathy, pulmonic stenosis, atrial septal defect, ventricular septal defect and patent ductus arteriosus (Aoki et al., 2013). The M90I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M90I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M90I as a disease-causing variant.
ClinVar Genomic variation as it relates to human health
NM_006912.6(RIT1):c.270G>T (p.Met90Ile)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006912.6(RIT1):c.270G>T (p.Met90Ile)
Variation ID: 265328 Accession: VCV000265328.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q22 1: 155904470 (GRCh38) [ NCBI UCSC ] 1: 155874261 (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 Oct 10, 2016 Feb 14, 2024 Apr 11, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006912.6:c.270G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008843.1:p.Met90Ile missense NM_001256820.2:c.162G>T NP_001243749.1:p.Met54Ile missense NM_001256821.2:c.321G>T NP_001243750.1:p.Met107Ile missense NC_000001.11:g.155904470C>A NC_000001.10:g.155874261C>A NG_033885.1:g.11933G>T LRG_1372:g.11933G>T LRG_1372t1:c.270G>T LRG_1372p1:p.Met90Ile Q92963:p.Met90Ile - Protein change
- M90I, M107I, M54I
- Other names
- -
- Canonical SPDI
- NC_000001.11:155904469:C:A
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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
Help
The frequency of the allele represented by this VCV record.
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- Links
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. |
|||
| RIT1 | - | - |
GRCh38 GRCh37 |
318 | 343 | |
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 (3) |
criteria provided, single submitter
|
Mar 27, 2017 | RCV000255338.5 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 11, 2023 | RCV000722172.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 27, 2019 | RCV001267162.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Mar 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322095.8
First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016 |
Comment:
The M90I variant in the RIT1 gene has been reported previously in a Noonan syndrome cohort as a de novo change in an individual with … (more)
The M90I variant in the RIT1 gene has been reported previously in a Noonan syndrome cohort as a de novo change in an individual with hypertrophic cardiomyopathy, pulmonic stenosis, atrial septal defect, ventricular septal defect and patent ductus arteriosus (Aoki et al., 2013). The M90I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M90I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M90I as a disease-causing variant. (less)
|
|
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Pathogenic
(Nov 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445343.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Cryptorchidism (present) , Pulmonic stenosis (disease) (present) , Hypoplastic aortic arch (present) , Patent foramen ovale (present) , Atrial septal defect (present) , Broad face … (more)
Cryptorchidism (present) , Pulmonic stenosis (disease) (present) , Hypoplastic aortic arch (present) , Patent foramen ovale (present) , Atrial septal defect (present) , Broad face (present) , Abnormality of the anterior fontanelle (present) , Hypertelorism (present) , Prominent forehead (present) , Dolichocephaly (present) , Abnormality of the palpebral fissures (present) , Proptosis (present) , Shallow orbits (present) , Anteverted ears (present) , Short ear (present) , Overfolded helix (present) , Narrow internal auditory canal (present) , Low posterior hairline (present) , Wide nasal bridge (present) , Midface retrusion (present) , Triangular face (present) , Short neck (present) , Wide intermamillary distance (present) , Sacral dimple (present) (less)
Sex: male
Ethnicity/Population group: Hispanic
|
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Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 8
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004050464.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
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Pathogenic
(Dec 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 8
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002239119.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the Met90 amino acid residue in RIT1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the Met90 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27109146, 29734338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 265328). This missense change has been observed in individual(s) with Noonan spectrum disorder (PMID: 23791108, 30692697). 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 methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile). (less)
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Pathogenic
(Nov 18, 2018)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome 8
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000854625.1
First in ClinVar: Dec 07, 2018 Last updated: Dec 07, 2018 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739815.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957708.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the Met90 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27109146, 29734338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 265328). This missense change has been observed in individual(s) with Noonan spectrum disorder (PMID: 23791108, 30692697). 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 methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile).
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:
The M90I variant in the RIT1 gene has been reported previously in a Noonan syndrome cohort as a de novo change in an individual with hypertrophic cardiomyopathy, pulmonic stenosis, atrial septal defect, ventricular septal defect and patent ductus arteriosus (Aoki et al., 2013). The M90I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M90I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M90I as a disease-causing variant.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the Met90 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27109146, 29734338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 265328). This missense change has been observed in individual(s) with Noonan spectrum disorder (PMID: 23791108, 30692697). 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 methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 90 of the RIT1 protein (p.Met90Ile).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort. | Chen H | Orphanet journal of rare diseases | 2019 | PMID: 30732632 |
| Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA. | Zhang J | Nature medicine | 2019 | PMID: 30692697 |
| RIT1 controls actin dynamics via complex formation with RAC1/CDC42 and PAK1. | Meyer Zum Büschenfelde U | PLoS genetics | 2018 | PMID: 29734338 |
| Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature. | Milosavljević D | American journal of medical genetics. Part A | 2016 | PMID: 27109146 |
| Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. | Yaoita M | Human genetics | 2016 | PMID: 26714497 |
| Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype. | Koenighofer M | Clinical genetics | 2016 | PMID: 25959749 |
| Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: four new cases and further evidence of heterogeneity. | Gos M | American journal of medical genetics. Part A | 2014 | PMID: 24939608 |
| Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. | Aoki Y | American journal of human genetics | 2013 | PMID: 23791108 |
Text-mined citations for rs483352822 ...
HelpThese 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 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.