Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with atherosclerosis undergoing whole exome sequencing (PMID: 22703879); This variant is associated with the following publications: (PMID: 14633923, 22703879)
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.509C>T (p.Thr170Ile)
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.
Uncertain significance
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_020975.6(RET):c.509C>T (p.Thr170Ile)
Variation ID: 41844 Accession: VCV000041844.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43102513 (GRCh38) [ NCBI UCSC ] 10: 43597961 (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 Apr 12, 2013 Nov 3, 2024 Feb 28, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.509C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Thr170Ile missense NM_000323.2:c.509C>T NP_000314.1:p.Thr170Ile missense NM_001406743.1:c.509C>T NP_001393672.1:p.Thr170Ile missense NM_001406744.1:c.509C>T NP_001393673.1:p.Thr170Ile missense NM_001406759.1:c.509C>T NP_001393688.1:p.Thr170Ile missense NM_001406760.1:c.509C>T NP_001393689.1:p.Thr170Ile missense NM_001406761.1:c.380C>T NP_001393690.1:p.Thr127Ile missense NM_001406762.1:c.380C>T NP_001393691.1:p.Thr127Ile missense NM_001406763.1:c.509C>T NP_001393692.1:p.Thr170Ile missense NM_001406764.1:c.380C>T NP_001393693.1:p.Thr127Ile missense NM_001406765.1:c.509C>T NP_001393694.1:p.Thr170Ile missense NM_001406768.1:c.380C>T NP_001393697.1:p.Thr127Ile missense NM_001406769.1:c.509C>T NP_001393698.1:p.Thr170Ile missense NM_001406771.1:c.509C>T NP_001393700.1:p.Thr170Ile missense NM_001406772.1:c.509C>T NP_001393701.1:p.Thr170Ile missense NM_001406773.1:c.509C>T NP_001393702.1:p.Thr170Ile missense NM_001406774.1:c.380C>T NP_001393703.1:p.Thr127Ile missense NM_001406779.1:c.509C>T NP_001393708.1:p.Thr170Ile missense NM_001406780.1:c.509C>T NP_001393709.1:p.Thr170Ile missense NM_001406781.1:c.509C>T NP_001393710.1:p.Thr170Ile missense NM_001406782.1:c.509C>T NP_001393711.1:p.Thr170Ile missense NM_001406783.1:c.380C>T NP_001393712.1:p.Thr127Ile missense NM_001406785.1:c.509C>T NP_001393714.1:p.Thr170Ile missense NM_001406786.1:c.380C>T NP_001393715.1:p.Thr127Ile missense NM_001406787.1:c.509C>T NP_001393716.1:p.Thr170Ile missense NM_020629.2:c.509C>T NP_065680.1:p.Thr170Ile missense NM_020630.7:c.509C>T NP_065681.1:p.Thr170Ile missense NC_000010.11:g.43102513C>T NC_000010.10:g.43597961C>T NG_007489.1:g.30445C>T LRG_518:g.30445C>T LRG_518t1:c.509C>T LRG_518p1:p.Thr170Ile LRG_518t2:c.509C>T LRG_518p2:p.Thr170Ile - Protein change
- T170I, T127I
- Other names
- -
- Canonical SPDI
- NC_000010.11:43102512:C: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.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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 (2) |
criteria provided, single submitter
|
Dec 29, 2023 | RCV000034776.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 28, 2016 | RCV000410582.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 28, 2024 | RCV001023532.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 28, 2016 | RCV000411681.3 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 8, 2023 | RCV000701145.11 |
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 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005383994.1
First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with atherosclerosis undergoing whole exome sequencing (PMID: 22703879); This variant is associated with the following publications: (PMID: 14633923, 22703879) (less)
|
|
|
Uncertain significance
(Jul 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489905.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Jul 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489906.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Dec 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000829929.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 170 of the RET protein (p.Thr170Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 170 of the RET protein (p.Thr170Ile). This variant is present in population databases (rs200547906, gnomAD 0.004%). 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: 41844). 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 tolerated. 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
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004827582.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Feb 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001185431.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.T170I variant (also known as c.509C>T), located in coding exon 3 of the RET gene, results from a C to T substitution at nucleotide … (more)
The p.T170I variant (also known as c.509C>T), located in coding exon 3 of the RET gene, results from a C to T substitution at nucleotide position 509. The threonine at codon 170 is replaced by isoleucine, an amino acid with similar properties. This variant was detected as a secondary finding in one out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
variant of unknown significance
(Jul 13, 2012)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043469.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
|
Comment:
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 170 of the RET protein (p.Thr170Ile). This variant is present in population databases (rs200547906, gnomAD 0.004%). 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: 41844). 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 tolerated. 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.T170I variant (also known as c.509C>T), located in coding exon 3 of the RET gene, results from a C to T substitution at nucleotide position 509. The threonine at codon 170 is replaced by isoleucine, an amino acid with similar properties. This variant was detected as a secondary finding in one out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Converted during submission to Uncertain significance.
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 does not alter protein structure/function; Observed in an individual with atherosclerosis undergoing whole exome sequencing (PMID: 22703879); This variant is associated with the following publications: (PMID: 14633923, 22703879)
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 170 of the RET protein (p.Thr170Ile). This variant is present in population databases (rs200547906, gnomAD 0.004%). 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: 41844). 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 tolerated. 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.T170I variant (also known as c.509C>T), located in coding exon 3 of the RET gene, results from a C to T substitution at nucleotide position 509. The threonine at codon 170 is replaced by isoleucine, an amino acid with similar properties. This variant was detected as a secondary finding in one out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Converted during submission to Uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Text-mined citations for rs200547906 ...
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 Nov 03, 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.