Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16758654, 24336963, 28188106, 14633923)
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2735G>T (p.Arg912Leu)
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.
(3)
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.
Uncertain significance
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020975.6(RET):c.2735G>T (p.Arg912Leu)
Variation ID: 543737 Accession: VCV000543737.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43121950 (GRCh38) [ NCBI UCSC ] 10: 43617398 (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 May 28, 2018 May 1, 2024 Jan 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2735G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg912Leu missense NM_000323.2:c.2735G>T NP_000314.1:p.Arg912Leu missense NM_001355216.2:c.1973G>T NP_001342145.1:p.Arg658Leu missense NM_001406743.1:c.2735G>T NP_001393672.1:p.Arg912Leu missense NM_001406744.1:c.2735G>T NP_001393673.1:p.Arg912Leu missense NM_001406759.1:c.2735G>T NP_001393688.1:p.Arg912Leu missense NM_001406760.1:c.2735G>T NP_001393689.1:p.Arg912Leu missense NM_001406761.1:c.2606G>T NP_001393690.1:p.Arg869Leu missense NM_001406762.1:c.2606G>T NP_001393691.1:p.Arg869Leu missense NM_001406763.1:c.2600G>T NP_001393692.1:p.Arg867Leu missense NM_001406764.1:c.2606G>T NP_001393693.1:p.Arg869Leu missense NM_001406765.1:c.2600G>T NP_001393694.1:p.Arg867Leu missense NM_001406766.1:c.2447G>T NP_001393695.1:p.Arg816Leu missense NM_001406767.1:c.2447G>T NP_001393696.1:p.Arg816Leu missense NM_001406768.1:c.2471G>T NP_001393697.1:p.Arg824Leu missense NM_001406769.1:c.2339G>T NP_001393698.1:p.Arg780Leu missense NM_001406770.1:c.2447G>T NP_001393699.1:p.Arg816Leu missense NM_001406771.1:c.2297G>T NP_001393700.1:p.Arg766Leu missense NM_001406772.1:c.2339G>T NP_001393701.1:p.Arg780Leu missense NM_001406773.1:c.2297G>T NP_001393702.1:p.Arg766Leu missense NM_001406774.1:c.2210G>T NP_001393703.1:p.Arg737Leu missense NM_001406775.1:c.2009G>T NP_001393704.1:p.Arg670Leu missense NM_001406776.1:c.2009G>T NP_001393705.1:p.Arg670Leu missense NM_001406777.1:c.2009G>T NP_001393706.1:p.Arg670Leu missense NM_001406778.1:c.2009G>T NP_001393707.1:p.Arg670Leu missense NM_001406779.1:c.1838G>T NP_001393708.1:p.Arg613Leu missense NM_001406780.1:c.1838G>T NP_001393709.1:p.Arg613Leu missense NM_001406781.1:c.1838G>T NP_001393710.1:p.Arg613Leu missense NM_001406782.1:c.1838G>T NP_001393711.1:p.Arg613Leu missense NM_001406783.1:c.1709G>T NP_001393712.1:p.Arg570Leu missense NM_001406784.1:c.1745G>T NP_001393713.1:p.Arg582Leu missense NM_001406785.1:c.1718G>T NP_001393714.1:p.Arg573Leu missense NM_001406786.1:c.1709G>T NP_001393715.1:p.Arg570Leu missense NM_001406787.1:c.1703G>T NP_001393716.1:p.Arg568Leu missense NM_001406788.1:c.1550G>T NP_001393717.1:p.Arg517Leu missense NM_001406789.1:c.1550G>T NP_001393718.1:p.Arg517Leu missense NM_001406790.1:c.1550G>T NP_001393719.1:p.Arg517Leu missense NM_001406791.1:c.1430G>T NP_001393720.1:p.Arg477Leu missense NM_001406792.1:c.1286G>T NP_001393721.1:p.Arg429Leu missense NM_001406793.1:c.1286G>T NP_001393722.1:p.Arg429Leu missense NM_001406794.1:c.1286G>T NP_001393723.1:p.Arg429Leu missense NM_020629.2:c.2735G>T NP_065680.1:p.Arg912Leu missense NM_020630.7:c.2735G>T NP_065681.1:p.Arg912Leu missense NC_000010.11:g.43121950G>T NC_000010.10:g.43617398G>T NG_007489.1:g.49882G>T LRG_518:g.49882G>T LRG_518t1:c.2735G>T LRG_518p1:p.Arg912Leu LRG_518t2:c.2735G>T LRG_518p2:p.Arg912Leu - Protein change
- R912L, R658L, R582L, R670L, R429L, R780L, R816L, R867L, R570L, R573L, R477L, R517L, R568L, R613L, R737L, R766L, R824L, R869L
- Other names
- -
- Canonical SPDI
- NC_000010.11:43121949:G:T
-
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.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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. |
|||
| RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3595 | 3717 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 16, 2024 | RCV000654572.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 23, 2023 | RCV002440388.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 22, 2022 | RCV003238798.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Dec 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003936365.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16758654, 24336963, 28188106, 14633923) (less)
|
|
|
Uncertain significance
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000776466.6
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 912 of the RET protein (p.Arg912Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 912 of the RET protein (p.Arg912Leu). This variant is present in population databases (rs78347871, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 543737). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. (less)
|
|
|
Uncertain significance
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002747762.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R912L variant (also known as c.2735G>T), located in coding exon 16 of the RET gene, results from a G to T substitution at nucleotide … (more)
The p.R912L variant (also known as c.2735G>T), located in coding exon 16 of the RET gene, results from a G to T substitution at nucleotide position 2735. The arginine at codon 912 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a MEN2-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. (less)
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 912 of the RET protein (p.Arg912Leu). This variant is present in population databases (rs78347871, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 543737). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Comment:
The p.R912L variant (also known as c.2735G>T), located in coding exon 16 of the RET gene, results from a G to T substitution at nucleotide position 2735. The arginine at codon 912 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a MEN2-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.
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:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16758654, 24336963, 28188106, 14633923)
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 912 of the RET protein (p.Arg912Leu). This variant is present in population databases (rs78347871, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 543737). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Comment:
The p.R912L variant (also known as c.2735G>T), located in coding exon 16 of the RET gene, results from a G to T substitution at nucleotide position 2735. The arginine at codon 912 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a MEN2-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach. | George Priya Doss C | Molecular bioSystems | 2014 | PMID: 24336963 |
Text-mined citations for rs78347871 ...
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.