ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1998delinsTTCT (p.Lys666delinsAsnSer)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.1998delinsTTCT (p.Lys666delinsAsnSer)
Variation ID: 1897685 Accession: VCV001897685.4
- Type and length
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Indel, 4 bp
- Location
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Cytogenetic: 10q11.21 10: 43114598 (GRCh38) [ NCBI UCSC ] 10: 43610046 (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 Feb 7, 2023 May 1, 2024 Jan 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.1998delinsTTCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Lys666delinsAsnSer inframe indel NM_000323.2:c.1998delGinsTTCT NP_000314.1:p.Lys666delinsAsnSer inframe indel NM_001355216.2:c.1236delGinsTTCT NP_001342145.1:p.Lys412delinsAsnSer inframe indel NM_001406743.1:c.1998delGinsTTCT NP_001393672.1:p.Lys666delinsAsnSer inframe indel NM_001406744.1:c.1998delGinsTTCT NP_001393673.1:p.Lys666delinsAsnSer inframe indel NM_001406759.1:c.1998delGinsTTCT NP_001393688.1:p.Lys666delinsAsnSer inframe indel NM_001406760.1:c.1998delGinsTTCT NP_001393689.1:p.Lys666delinsAsnSer inframe indel NM_001406761.1:c.1869delGinsTTCT NP_001393690.1:p.Lys623delinsAsnSer inframe indel NM_001406762.1:c.1869delGinsTTCT NP_001393691.1:p.Lys623delinsAsnSer inframe indel NM_001406764.1:c.1869delGinsTTCT NP_001393693.1:p.Lys623delinsAsnSer inframe indel NM_001406766.1:c.1710delGinsTTCT NP_001393695.1:p.Lys570delinsAsnSer inframe indel NM_001406767.1:c.1710delGinsTTCT NP_001393696.1:p.Lys570delinsAsnSer inframe indel NM_001406769.1:c.1602delGinsTTCT NP_001393698.1:p.Lys534delinsAsnSer inframe indel NM_001406770.1:c.1710delGinsTTCT NP_001393699.1:p.Lys570delinsAsnSer inframe indel NM_001406771.1:c.1560delGinsTTCT NP_001393700.1:p.Lys520delinsAsnSer inframe indel NM_001406772.1:c.1602delGinsTTCT NP_001393701.1:p.Lys534delinsAsnSer inframe indel NM_001406773.1:c.1560delGinsTTCT NP_001393702.1:p.Lys520delinsAsnSer inframe indel NM_001406774.1:c.1473delGinsTTCT NP_001393703.1:p.Lys491delinsAsnSer inframe indel NM_001406775.1:c.1272delGinsTTCT NP_001393704.1:p.Lys424delinsAsnSer inframe indel NM_001406776.1:c.1272delGinsTTCT NP_001393705.1:p.Lys424delinsAsnSer inframe indel NM_001406777.1:c.1272delGinsTTCT NP_001393706.1:p.Lys424delinsAsnSer inframe indel NM_001406778.1:c.1272delGinsTTCT NP_001393707.1:p.Lys424delinsAsnSer inframe indel NM_001406779.1:c.1101delGinsTTCT NP_001393708.1:p.Lys367delinsAsnSer inframe indel NM_001406780.1:c.1101delGinsTTCT NP_001393709.1:p.Lys367delinsAsnSer inframe indel NM_001406781.1:c.1101delGinsTTCT NP_001393710.1:p.Lys367delinsAsnSer inframe indel NM_001406782.1:c.1101delGinsTTCT NP_001393711.1:p.Lys367delinsAsnSer inframe indel NM_001406783.1:c.972delGinsTTCT NP_001393712.1:p.Lys324delinsAsnSer inframe indel NM_001406784.1:c.1008delGinsTTCT NP_001393713.1:p.Lys336delinsAsnSer inframe indel NM_001406785.1:c.981delGinsTTCT NP_001393714.1:p.Lys327delinsAsnSer inframe indel NM_001406786.1:c.972delGinsTTCT NP_001393715.1:p.Lys324delinsAsnSer inframe indel NM_001406788.1:c.813delGinsTTCT NP_001393717.1:p.Lys271delinsAsnSer inframe indel NM_001406789.1:c.813delGinsTTCT NP_001393718.1:p.Lys271delinsAsnSer inframe indel NM_001406790.1:c.813delGinsTTCT NP_001393719.1:p.Lys271delinsAsnSer inframe indel NM_001406791.1:c.693delGinsTTCT NP_001393720.1:p.Lys231delinsAsnSer inframe indel NM_001406792.1:c.549delGinsTTCT NP_001393721.1:p.Lys183delinsAsnSer inframe indel NM_001406793.1:c.549delGinsTTCT NP_001393722.1:p.Lys183delinsAsnSer inframe indel NM_001406794.1:c.549delGinsTTCT NP_001393723.1:p.Lys183delinsAsnSer inframe indel NM_020629.2:c.1998delGinsTTCT NP_065680.1:p.Lys666delinsAsnSer inframe indel NM_020630.7:c.1998delGinsTTCT NP_065681.1:p.Lys666delinsAsnSer inframe indel NC_000010.11:g.43114598delinsTTCT NC_000010.10:g.43610046delinsTTCT NG_007489.1:g.42530delGinsTTCT NG_007489.1:g.42530delinsTTCT LRG_518:g.42530delinsTTCT LRG_518t1:c.1998delGinsTTCT LRG_518p1:p.Lys666delinsAsnSer LRG_518t2:c.1998delGinsTTCT LRG_518p2:p.Lys666delinsAsnSer - Protein change
- Other names
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- Canonical SPDI
- NC_000010.11:43114597:G:TTCT
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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.
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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 | ||
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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
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. |
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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3528 | 3648 |
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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May 29, 2023 | RCV002572537.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV004064341.1 |
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. |
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Likely pathogenic
(May 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002933036.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This variant, c.1998delinsTTCT , is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the RET … (more)
This variant, c.1998delinsTTCT , is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the RET protein (p.Lys666delinsAsnSer). 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. Experimental studies have shown that this variant affects RET function (PMID: 16954442). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant is also known as c.2646delGinsTTCT or Lys666Asn, ins Ser. This variant has been observed in individuals with familial medullary thyroid carcinoma (PMID: 1694442, 15844786, 16954442; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). (less)
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Likely pathogenic
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004930779.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16954442]. This variant has been reported in multiple individuals with … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16954442]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16954442, 15844786, 17639053, 27673361, 29408964, 20103606]. (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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A Homozygous RET K666N Genotype With an MEN2A Phenotype. | Jaber T | The Journal of clinical endocrinology and metabolism | 2018 | PMID: 29408964 |
Medullary Thyroid Carcinoma Associated with Germline RET(K666N) Mutation. | Xu JY | Thyroid : official journal of the American Thyroid Association | 2016 | PMID: 27673361 |
Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro. | Muzza M | European journal of endocrinology | 2010 | PMID: 20103606 |
Histopathological and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? | Verga U | Endocrine-related cancer | 2007 | PMID: 17639053 |
Medullary thyroid carcinoma in a child with a new RET mutation and a RET polymorphism. | Vandenbosch K | Genetic counseling (Geneva, Switzerland) | 2005 | PMID: 15844786 |
On the use of normal modes in thermal parameter refinement: theory and application to the bovine pancreatic trypsin inhibitor. | Diamond R | Acta crystallographica. Section A, Foundations of crystallography | 1990 | PMID: 1694442 |
Text-mined citations for rs377767440 ...
HelpRecord last updated Jun 30, 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.