ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2162G>A (p.Arg721Gln)
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.2162G>A (p.Arg721Gln)
Variation ID: 584563 Accession: VCV000584563.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43116609 (GRCh38) [ NCBI UCSC ] 10: 43612057 (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 Oct 10, 2018 Feb 14, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2162G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg721Gln missense NM_000323.2:c.2162G>A NP_000314.1:p.Arg721Gln missense NM_001355216.2:c.1400G>A NP_001342145.1:p.Arg467Gln missense NM_001406743.1:c.2162G>A NP_001393672.1:p.Arg721Gln missense NM_001406744.1:c.2162G>A NP_001393673.1:p.Arg721Gln missense NM_001406759.1:c.2162G>A NP_001393688.1:p.Arg721Gln missense NM_001406760.1:c.2162G>A NP_001393689.1:p.Arg721Gln missense NM_001406761.1:c.2033G>A NP_001393690.1:p.Arg678Gln missense NM_001406762.1:c.2033G>A NP_001393691.1:p.Arg678Gln missense NM_001406763.1:c.2027G>A NP_001393692.1:p.Arg676Gln missense NM_001406764.1:c.2033G>A NP_001393693.1:p.Arg678Gln missense NM_001406765.1:c.2027G>A NP_001393694.1:p.Arg676Gln missense NM_001406766.1:c.1874G>A NP_001393695.1:p.Arg625Gln missense NM_001406767.1:c.1874G>A NP_001393696.1:p.Arg625Gln missense NM_001406768.1:c.1898G>A NP_001393697.1:p.Arg633Gln missense NM_001406769.1:c.1766G>A NP_001393698.1:p.Arg589Gln missense NM_001406770.1:c.1874G>A NP_001393699.1:p.Arg625Gln missense NM_001406771.1:c.1724G>A NP_001393700.1:p.Arg575Gln missense NM_001406772.1:c.1766G>A NP_001393701.1:p.Arg589Gln missense NM_001406773.1:c.1724G>A NP_001393702.1:p.Arg575Gln missense NM_001406774.1:c.1637G>A NP_001393703.1:p.Arg546Gln missense NM_001406775.1:c.1436G>A NP_001393704.1:p.Arg479Gln missense NM_001406776.1:c.1436G>A NP_001393705.1:p.Arg479Gln missense NM_001406777.1:c.1436G>A NP_001393706.1:p.Arg479Gln missense NM_001406778.1:c.1436G>A NP_001393707.1:p.Arg479Gln missense NM_001406779.1:c.1265G>A NP_001393708.1:p.Arg422Gln missense NM_001406780.1:c.1265G>A NP_001393709.1:p.Arg422Gln missense NM_001406781.1:c.1265G>A NP_001393710.1:p.Arg422Gln missense NM_001406782.1:c.1265G>A NP_001393711.1:p.Arg422Gln missense NM_001406783.1:c.1136G>A NP_001393712.1:p.Arg379Gln missense NM_001406784.1:c.1172G>A NP_001393713.1:p.Arg391Gln missense NM_001406785.1:c.1145G>A NP_001393714.1:p.Arg382Gln missense NM_001406786.1:c.1136G>A NP_001393715.1:p.Arg379Gln missense NM_001406787.1:c.1130G>A NP_001393716.1:p.Arg377Gln missense NM_001406788.1:c.977G>A NP_001393717.1:p.Arg326Gln missense NM_001406789.1:c.977G>A NP_001393718.1:p.Arg326Gln missense NM_001406790.1:c.977G>A NP_001393719.1:p.Arg326Gln missense NM_001406791.1:c.857G>A NP_001393720.1:p.Arg286Gln missense NM_001406792.1:c.713G>A NP_001393721.1:p.Arg238Gln missense NM_001406793.1:c.713G>A NP_001393722.1:p.Arg238Gln missense NM_001406794.1:c.713G>A NP_001393723.1:p.Arg238Gln missense NM_020629.2:c.2162G>A NP_065680.1:p.Arg721Gln missense NM_020630.7:c.2162G>A NP_065681.1:p.Arg721Gln missense NC_000010.11:g.43116609G>A NC_000010.10:g.43612057G>A NG_007489.1:g.44541G>A LRG_518:g.44541G>A LRG_518t1:c.2162G>A LRG_518p1:p.Arg721Gln LRG_518t2:c.2162G>A LRG_518p2:p.Arg721Gln - Protein change
- R721Q, R467Q, R286Q, R377Q, R479Q, R625Q, R379Q, R391Q, R589Q, R676Q, R326Q, R422Q, R678Q, R238Q, R382Q, R546Q, R575Q, R633Q
- Other names
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- Canonical SPDI
- NC_000010.11:43116608: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
3382 | 3500 |
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. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2022 | RCV000708757.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 23, 2023 | RCV001205883.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 25, 2023 | RCV001545206.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 23, 2021 | RCV002485780.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV003460990.1 |
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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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000822196.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Sep 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Familial medullary thyroid carcinoma Multiple endocrine neoplasia, type 2b Pheochromocytoma Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002792704.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Nov 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003911393.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.R721Q variant (also known as c.2162G>A), located in coding exon 12 of the RET gene, results from a G to A substitution at nucleotide … (more)
The p.R721Q variant (also known as c.2162G>A), located in coding exon 12 of the RET gene, results from a G to A substitution at nucleotide position 2162. The arginine at codon 721 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. (less)
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Uncertain significance
(Jul 25, 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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GeneDx
Accession: SCV001764488.2
First in ClinVar: Aug 07, 2021 Last updated: Aug 05, 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; Observed in individuals with personal or family history of breast/ovarian or other cancers (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 31159747, 14633923) (less)
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Uncertain significance
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208637.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(May 23, 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: SCV001377163.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. 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. ClinVar contains an entry for this variant (Variation ID: 584563). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 721 of the RET protein (p.Arg721Gln). (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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Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Text-mined citations for rs1356141763 ...
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.