ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2755G>C (p.Ala919Pro)
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.2755G>C (p.Ala919Pro)
Variation ID: 581770 Accession: VCV000581770.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43121970 (GRCh38) [ NCBI UCSC ] 10: 43617418 (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 May 1, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2755G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Ala919Pro missense NM_000323.2:c.2755G>C NP_000314.1:p.Ala919Pro missense NM_001355216.2:c.1993G>C NP_001342145.1:p.Ala665Pro missense NM_001406743.1:c.2755G>C NP_001393672.1:p.Ala919Pro missense NM_001406744.1:c.2755G>C NP_001393673.1:p.Ala919Pro missense NM_001406759.1:c.2755G>C NP_001393688.1:p.Ala919Pro missense NM_001406760.1:c.2755G>C NP_001393689.1:p.Ala919Pro missense NM_001406761.1:c.2626G>C NP_001393690.1:p.Ala876Pro missense NM_001406762.1:c.2626G>C NP_001393691.1:p.Ala876Pro missense NM_001406763.1:c.2620G>C NP_001393692.1:p.Ala874Pro missense NM_001406764.1:c.2626G>C NP_001393693.1:p.Ala876Pro missense NM_001406765.1:c.2620G>C NP_001393694.1:p.Ala874Pro missense NM_001406766.1:c.2467G>C NP_001393695.1:p.Ala823Pro missense NM_001406767.1:c.2467G>C NP_001393696.1:p.Ala823Pro missense NM_001406768.1:c.2491G>C NP_001393697.1:p.Ala831Pro missense NM_001406769.1:c.2359G>C NP_001393698.1:p.Ala787Pro missense NM_001406770.1:c.2467G>C NP_001393699.1:p.Ala823Pro missense NM_001406771.1:c.2317G>C NP_001393700.1:p.Ala773Pro missense NM_001406772.1:c.2359G>C NP_001393701.1:p.Ala787Pro missense NM_001406773.1:c.2317G>C NP_001393702.1:p.Ala773Pro missense NM_001406774.1:c.2230G>C NP_001393703.1:p.Ala744Pro missense NM_001406775.1:c.2029G>C NP_001393704.1:p.Ala677Pro missense NM_001406776.1:c.2029G>C NP_001393705.1:p.Ala677Pro missense NM_001406777.1:c.2029G>C NP_001393706.1:p.Ala677Pro missense NM_001406778.1:c.2029G>C NP_001393707.1:p.Ala677Pro missense NM_001406779.1:c.1858G>C NP_001393708.1:p.Ala620Pro missense NM_001406780.1:c.1858G>C NP_001393709.1:p.Ala620Pro missense NM_001406781.1:c.1858G>C NP_001393710.1:p.Ala620Pro missense NM_001406782.1:c.1858G>C NP_001393711.1:p.Ala620Pro missense NM_001406783.1:c.1729G>C NP_001393712.1:p.Ala577Pro missense NM_001406784.1:c.1765G>C NP_001393713.1:p.Ala589Pro missense NM_001406785.1:c.1738G>C NP_001393714.1:p.Ala580Pro missense NM_001406786.1:c.1729G>C NP_001393715.1:p.Ala577Pro missense NM_001406787.1:c.1723G>C NP_001393716.1:p.Ala575Pro missense NM_001406788.1:c.1570G>C NP_001393717.1:p.Ala524Pro missense NM_001406789.1:c.1570G>C NP_001393718.1:p.Ala524Pro missense NM_001406790.1:c.1570G>C NP_001393719.1:p.Ala524Pro missense NM_001406791.1:c.1450G>C NP_001393720.1:p.Ala484Pro missense NM_001406792.1:c.1306G>C NP_001393721.1:p.Ala436Pro missense NM_001406793.1:c.1306G>C NP_001393722.1:p.Ala436Pro missense NM_001406794.1:c.1306G>C NP_001393723.1:p.Ala436Pro missense NM_020629.2:c.2755G>C NP_065680.1:p.Ala919Pro missense NM_020630.7:c.2755G>C NP_065681.1:p.Ala919Pro missense NC_000010.11:g.43121970G>C NC_000010.10:g.43617418G>C NG_007489.1:g.49902G>C LRG_518:g.49902G>C LRG_518t1:c.2755G>C LRG_518p1:p.Ala919Pro LRG_518t2:c.2755G>C LRG_518p2:p.Ala919Pro - Protein change
- A919P, A665P, A620P, A677P, A744P, A787P, A575P, A577P, A580P, A589P, A831P, A436P, A773P, A484P, A524P, A823P, A874P, A876P
- Other names
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- Canonical SPDI
- NC_000010.11:43121969:G:C
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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), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
3522 | 3642 |
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Nov 24, 2023 | RCV000705686.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 6, 2023 | RCV002440539.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 13, 2023 | RCV003403635.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 25, 2022 | RCV002485764.1 |
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
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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
(May 25, 2022)
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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 IIB Pheochromocytoma MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002789953.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Apr 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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RET-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004112166.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The RET c.2755G>C variant is predicted to result in the amino acid substitution p.Ala919Pro. This variant with a second RET1 missense variant was reported in … (more)
The RET c.2755G>C variant is predicted to result in the amino acid substitution p.Ala919Pro. This variant with a second RET1 missense variant was reported in a metastatic lymph node from a female patient with familial medullary thyroid cancer (Iwashita T et al 1999. PubMed ID: 10445857). Functional studies indicate this variant may alter protein function (Iwashita T et al 1999. PubMed ID: 10445857; Iwashita T et al 1999. PubMed ID: 10445857). This variant was also reported as a somatic variant of uncertain significance in a diffuse leptomeningeal glioneuronal tumor sample (Table 1 in Manoharan et al. 2021. PubMed ID: 34493325). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43617418-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Nov 24, 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: SCV000834695.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 919 of the RET protein (p.Ala919Pro). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 919 of the RET protein (p.Ala919Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 581770). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 10445857). 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)
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Uncertain significance
(Jun 06, 2023)
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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: SCV002749021.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.A919P variant (also known as c.2755G>C), located in coding exon 16 of the RET gene, results from a G to C substitution at nucleotide … (more)
The p.A919P variant (also known as c.2755G>C), located in coding exon 16 of the RET gene, results from a G to C substitution at nucleotide position 2755. The alanine at codon 919 is replaced by proline, an amino acid with highly similar properties. In one paper, this alteration was shown to have low transforming activity in vitro (Iwashita T, et al. Oncogene 1999;18(26):3919-22). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. | Plaza-Menacho I | Molecular cell | 2014 | PMID: 24560924 |
Minireview: RET: normal and abnormal functions. | Santoro M | Endocrinology | 2004 | PMID: 15331579 |
Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. | Iwashita T | Oncogene | 1999 | PMID: 10445857 |
A novel somatic mutation in the RET proto-oncogene in familial medullary thyroid carcinoma with a germline codon 768 mutation. | Miyauchi A | Japanese journal of cancer research : Gann | 1997 | PMID: 9263528 |
Text-mined citations for rs1361265737 ...
HelpRecord last updated May 01, 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.