ClinVar Genomic variation as it relates to human health
NM_002880.4(RAF1):c.1922C>T (p.Thr641Met)
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.
Pathogenic(3); Likely pathogenic(1); 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.1922C>T (p.Thr641Met)
Variation ID: 142298 Accession: VCV000142298.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.2 3: 12584539 (GRCh38) [ NCBI UCSC ] 3: 12626038 (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 Aug 29, 2016 Mar 10, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002880.4:c.1922C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002871.1:p.Thr641Met missense NM_001354689.3:c.1982C>T NP_001341618.1:p.Thr661Met missense NM_001354690.3:c.1922C>T NP_001341619.1:p.Thr641Met missense NM_001354691.3:c.1679C>T NP_001341620.1:p.Thr560Met missense NM_001354692.3:c.1679C>T NP_001341621.1:p.Thr560Met missense NM_001354693.3:c.1823C>T NP_001341622.1:p.Thr608Met missense NM_001354694.3:c.1739C>T NP_001341623.1:p.Thr580Met missense NM_001354695.3:c.1580C>T NP_001341624.1:p.Thr527Met missense NM_002880.3:c.[1922C>T] NR_148940.3:n.2366C>T non-coding transcript variant NR_148941.3:n.2312C>T non-coding transcript variant NR_148942.3:n.2251C>T non-coding transcript variant NC_000003.12:g.12584539G>A NC_000003.11:g.12626038G>A NG_007467.1:g.84641C>T LRG_413:g.84641C>T LRG_413t1:c.1922C>T LRG_413p1:p.Thr641Met LRG_413t2:c.1982C>T LRG_413p2:p.Thr661Met P04049:p.Thr641Met - Protein change
- T641M, T580M, T608M, T560M, T661M, T527M
- Other names
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- Canonical SPDI
- NC_000003.12:12584538:G: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00001
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
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. |
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RAF1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1060 | 1117 |
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
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 (3) |
criteria provided, multiple submitters, no conflicts
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May 22, 2022 | RCV000131336.7 | |
Pathogenic (1) |
criteria provided, single submitter
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May 8, 2019 | RCV000852545.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV001657807.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2024 | RCV001849941.4 |
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
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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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Uncertain significance
(Mar 11, 2021)
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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: SCV001874005.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein … (more)
Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar, but additional evidence is not available (ClinVar Variant ID# 142298; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 24777450) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1NN
Affected status: yes
Allele origin:
germline
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Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine
Accession: SCV002073125.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.T641M in RAF1 (NM_002880.4) has been reported previously in patients affected with childhood onset cardiomyopathy (Dhandapany S et al). Functional studies in … (more)
The missense variant p.T641M in RAF1 (NM_002880.4) has been reported previously in patients affected with childhood onset cardiomyopathy (Dhandapany S et al). Functional studies in zebrafish revealed a heart failure phenotype. It has been submitted to the ClinVar database as Pathogenic. There is a moderate physicochemical difference between threonine and methionine. The p.T641M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 641 of RAF1 is conserved in all mammalian species. The nucleotide c.1922 in RAF1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Recurrent hypoglycemia (present) , Ketosis (present) , Microcephaly (present) , Delayed speech and language development (present) , Small for gestational age (present) , Decreased body … (more)
Recurrent hypoglycemia (present) , Ketosis (present) , Microcephaly (present) , Delayed speech and language development (present) , Small for gestational age (present) , Decreased body weight (present) (less)
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1NN
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521400.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24777450). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000142298). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Congestive heart failure (present)
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Pathogenic
(May 08, 2019)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995244.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 27, 2024)
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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: SCV002291943.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 641 of the RAF1 protein (p.Thr641Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 641 of the RAF1 protein (p.Thr641Met). This variant is present in population databases (rs587777587, gnomAD 0.006%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 24777450). ClinVar contains an entry for this variant (Variation ID: 142298). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAF1 protein function. Experimental studies have shown that this missense change affects RAF1 function (PMID: 24777450). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Apr 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011445.5
First in ClinVar: Jul 16, 2023 Last updated: Mar 10, 2024 |
Comment:
RAF1: PS3:Moderate, PS4:Moderate, PM2:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, DILATED, 1NN
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000186310.2
First in ClinVar: Aug 06, 2014 Last updated: Aug 29, 2016 |
Comment on evidence:
In a 15-year-old South Indian girl and an unrelated 21-year-old North Indian man with nonsyndromic dilated cardiomyopathy (CMD1NN; 615916), Dhandapany et al. (2014) identified heterozygosity … (more)
In a 15-year-old South Indian girl and an unrelated 21-year-old North Indian man with nonsyndromic dilated cardiomyopathy (CMD1NN; 615916), Dhandapany et al. (2014) identified heterozygosity for a c.1922T-C transition in the RAF1 gene, resulting in a thr641-to-met (T641M) substitution at a highly conserved residue. Age at onset of disease in the 2 patients was 7 years and 16 years, respectively. The mutation, which segregated with disease in the available family, was not found in 500 ancestry-matched South Indian controls or in 350 ancestry-matched North Indian controls. Functional analysis in HEK293 cells showed a mild increase in kinase activity with the T641M mutant that was less augmented than that of the CMH-associated RAF1 mutants tested, L613V (164760.0004) and S257L (164760.0001). ERK (see 601795) activation with the T641M mutant was similar to that observed with wildtype RAF1 and was significantly less than with the CMH-associated mutants. (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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ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. | Gelb BD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29493581 |
RAF1 mutations in childhood-onset dilated cardiomyopathy. | Dhandapany PS | Nature genetics | 2014 | PMID: 24777450 |
Text-mined citations for rs587777587 ...
HelpRecord last updated Mar 11, 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.