ClinVar Genomic variation as it relates to human health
NM_002880.4(RAF1):c.1871C>G (p.Ser624Cys)
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.
Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002880.4(RAF1):c.1871C>G (p.Ser624Cys)
Variation ID: 391813 Accession: VCV000391813.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.2 3: 12584590 (GRCh38) [ NCBI UCSC ] 3: 12626089 (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 Sep 8, 2018 Feb 20, 2024 Aug 23, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002880.4:c.1871C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002871.1:p.Ser624Cys missense NM_001354689.3:c.1931C>G NP_001341618.1:p.Ser644Cys missense NM_001354690.3:c.1871C>G NP_001341619.1:p.Ser624Cys missense NM_001354691.3:c.1628C>G NP_001341620.1:p.Ser543Cys missense NM_001354692.3:c.1628C>G NP_001341621.1:p.Ser543Cys missense NM_001354693.3:c.1772C>G NP_001341622.1:p.Ser591Cys missense NM_001354694.3:c.1688C>G NP_001341623.1:p.Ser563Cys missense NM_001354695.3:c.1529C>G NP_001341624.1:p.Ser510Cys missense NR_148940.3:n.2315C>G non-coding transcript variant NR_148941.3:n.2261C>G non-coding transcript variant NR_148942.3:n.2200C>G non-coding transcript variant NC_000003.12:g.12584590G>C NC_000003.11:g.12626089G>C NG_007467.1:g.84590C>G LRG_413:g.84590C>G LRG_413t1:c.1871C>G LRG_413p1:p.Ser624Cys LRG_413t2:c.1931C>G LRG_413p2:p.Ser644Cys - Protein change
- S624C, S563C, S644C, S510C, S543C, S591C
- Other names
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- Canonical SPDI
- NC_000003.12:12584589:G:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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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RAF1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1060 | 1114 |
Conditions - Germline
Condition
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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
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 8, 2019 | RCV000678309.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 23, 2022 | RCV001051449.8 |
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
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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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Likely pathogenic
(Aug 14, 2018)
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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: SCV000534967.4
First in ClinVar: Mar 08, 2017 Last updated: Sep 21, 2018 |
Comment:
The S624C variant in the RAF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The S624C variant in the RAF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S624C variant was not observed in approximately 6,500 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 S624C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S624C as a likely pathogenic variant. (less)
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Likely pathogenic
(Jul 08, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714079.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS4_Supporting PM1, PM2, PP2, PP3
Number of individuals with the variant: 1
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Uncertain significance
(Feb 26, 2018)
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criteria provided, single submitter
Method: provider interpretation, clinical testing
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Not Provided
Affected status: unknown
Allele origin:
paternal
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Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804368.2
First in ClinVar: Sep 08, 2018 Last updated: Dec 11, 2022 |
Comment:
This variant was identified in a 3 year male with autism spectrum disorder and tall stature. Clinical features were not consistent with a Noonan-spectrum disorder. … (more)
This variant was identified in a 3 year male with autism spectrum disorder and tall stature. Clinical features were not consistent with a Noonan-spectrum disorder. The variant is inherited from a father with no development delay, psychiatric illness, or other relevant history. Subsequent cardiology evaluation was normal and the father had a normal cardiac stress test with echocardiogram. This variant is absent from the gnomAD database and computational prediction models are inconsistent. It has not been previously reported in the literature, to our knowledge. (less)
Observation 1:
Clinical Features:
Autistic disorder of childhood onset (present) , Tall stature (present)
Age: 0-9 years
Sex: male
Secondary finding: no
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-01-13
Testing laboratory interpretation: Uncertain significance
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Autistic disorder of childhood onset (present) , Tall stature (present)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-01-13
Testing laboratory interpretation: Uncertain significance
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Uncertain significance
(Aug 23, 2022)
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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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Invitae
Accession: SCV001215603.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 624 of the RAF1 protein … (more)
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 624 of the RAF1 protein (p.Ser624Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. 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 RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 391813). (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
HelpThere 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 rs1057524239 ...
HelpRecord last updated Feb 20, 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.