ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2330A>G (p.Asn777Ser)
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.2330A>G (p.Asn777Ser)
Variation ID: 24937 Accession: VCV000024937.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43118418 (GRCh38) [ NCBI UCSC ] 10: 43613866 (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 Apr 4, 2013 Apr 15, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2330A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Asn777Ser missense NM_000323.2:c.2330A>G NP_000314.1:p.Asn777Ser missense NM_001355216.2:c.1568A>G NP_001342145.1:p.Asn523Ser missense NM_001406743.1:c.2330A>G NP_001393672.1:p.Asn777Ser missense NM_001406744.1:c.2330A>G NP_001393673.1:p.Asn777Ser missense NM_001406759.1:c.2330A>G NP_001393688.1:p.Asn777Ser missense NM_001406760.1:c.2330A>G NP_001393689.1:p.Asn777Ser missense NM_001406761.1:c.2201A>G NP_001393690.1:p.Asn734Ser missense NM_001406762.1:c.2201A>G NP_001393691.1:p.Asn734Ser missense NM_001406763.1:c.2195A>G NP_001393692.1:p.Asn732Ser missense NM_001406764.1:c.2201A>G NP_001393693.1:p.Asn734Ser missense NM_001406765.1:c.2195A>G NP_001393694.1:p.Asn732Ser missense NM_001406766.1:c.2042A>G NP_001393695.1:p.Asn681Ser missense NM_001406767.1:c.2042A>G NP_001393696.1:p.Asn681Ser missense NM_001406768.1:c.2066A>G NP_001393697.1:p.Asn689Ser missense NM_001406769.1:c.1934A>G NP_001393698.1:p.Asn645Ser missense NM_001406770.1:c.2042A>G NP_001393699.1:p.Asn681Ser missense NM_001406771.1:c.1892A>G NP_001393700.1:p.Asn631Ser missense NM_001406772.1:c.1934A>G NP_001393701.1:p.Asn645Ser missense NM_001406773.1:c.1892A>G NP_001393702.1:p.Asn631Ser missense NM_001406774.1:c.1805A>G NP_001393703.1:p.Asn602Ser missense NM_001406775.1:c.1604A>G NP_001393704.1:p.Asn535Ser missense NM_001406776.1:c.1604A>G NP_001393705.1:p.Asn535Ser missense NM_001406777.1:c.1604A>G NP_001393706.1:p.Asn535Ser missense NM_001406778.1:c.1604A>G NP_001393707.1:p.Asn535Ser missense NM_001406779.1:c.1433A>G NP_001393708.1:p.Asn478Ser missense NM_001406780.1:c.1433A>G NP_001393709.1:p.Asn478Ser missense NM_001406781.1:c.1433A>G NP_001393710.1:p.Asn478Ser missense NM_001406782.1:c.1433A>G NP_001393711.1:p.Asn478Ser missense NM_001406783.1:c.1304A>G NP_001393712.1:p.Asn435Ser missense NM_001406784.1:c.1340A>G NP_001393713.1:p.Asn447Ser missense NM_001406785.1:c.1313A>G NP_001393714.1:p.Asn438Ser missense NM_001406786.1:c.1304A>G NP_001393715.1:p.Asn435Ser missense NM_001406787.1:c.1298A>G NP_001393716.1:p.Asn433Ser missense NM_001406788.1:c.1145A>G NP_001393717.1:p.Asn382Ser missense NM_001406789.1:c.1145A>G NP_001393718.1:p.Asn382Ser missense NM_001406790.1:c.1145A>G NP_001393719.1:p.Asn382Ser missense NM_001406791.1:c.1025A>G NP_001393720.1:p.Asn342Ser missense NM_001406792.1:c.881A>G NP_001393721.1:p.Asn294Ser missense NM_001406793.1:c.881A>G NP_001393722.1:p.Asn294Ser missense NM_001406794.1:c.881A>G NP_001393723.1:p.Asn294Ser missense NM_020629.2:c.2330A>G NP_065680.1:p.Asn777Ser missense NM_020630.7:c.2330A>G NP_065681.1:p.Asn777Ser missense NC_000010.11:g.43118418A>G NC_000010.10:g.43613866A>G NG_007489.1:g.46350A>G LRG_518:g.46350A>G LRG_518t1:c.2330A>G LRG_518p1:p.Asn777Ser LRG_518t2:c.2330A>G LRG_518p2:p.Asn777Ser - Protein change
- N523S, N435S, N438S, N447S, N602S, N689S, N734S, N382S, N535S, N681S, N294S, N342S, N433S, N631S, N478S, N645S, N732S
- Other names
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- Canonical SPDI
- NC_000010.11:43118417:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Uncertain function
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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
Exome Aggregation Consortium (ExAC) 0.00001
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
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 |
3523 | 3643 |
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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Jul 2, 2018 | RCV000709121.10 | |
Uncertain significance (1) |
no assertion criteria provided
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Dec 17, 2020 | RCV001289997.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV001351342.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 30, 2023 | RCV002225073.10 |
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
(Jul 02, 2018)
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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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Mendelics
Accession: SCV000838399.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Oct 25, 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: SCV001545806.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 777 of the RET protein (p.Asn777Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 777 of the RET protein (p.Asn777Ser). This variant is present in population databases (rs377767415, gnomAD 0.0009%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 16384843). ClinVar contains an entry for this variant (Variation ID: 24937). 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 have shown that this missense change affects RET function (PMID: 16384843). 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
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial medullary thyroid carcinoma
Affected status: no
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503792.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace asparagine with serine at codon 777 of the RET protein (p.(Asn777Ser)). The asparagine residue is conserved in mammals, … (more)
This sequence change is predicted to replace asparagine with serine at codon 777 of the RET protein (p.(Asn777Ser)). The asparagine residue is conserved in mammals, birds, and reptiles (100 vertebrates, UCSC), and is located in the protein tyrosine domain (UniProt). There is a small physicochemical difference between asparagine and serine. The variant is present in a single individual in a large population cohort (PM2; 1/251,332 alleles in gnomAD v2.1), and has been reported as a variant of uncertain significance in ClinVar (ID: 24937). The variant has been identified in an individual with late onset medullary thyroid cancer with limited aggressiveness (PMID: 16384843) and as an incidental finding in a single case in a paediatric cohort with various indications for testing (PMID: 31937788). The missense change has low-grade transforming potential and limited activation of RET tyrosine kinase in functional assays (PS3_Supporting; PMID: 16384843). Multiple lines of computational evidence predict a benign effect for the missense substitution, but may affect other protein features (4/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2, PS3_Supporting. (less)
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Uncertain significance
(Dec 17, 2020)
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no assertion criteria provided
Method: case-control
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Appendicitis
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Klinik und Poliklinik für Kinderchirurgie, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus
Accession: SCV001469010.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Clinical Features:
OMIM:107700 (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Dresden
Geographic origin: Germany
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain function
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Klinik und Poliklinik für Kinderchirurgie, Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus
Accession: SCV001469010.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels. | Chirita-Emandi A | Scientific reports | 2020 | PMID: 31937788 |
Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma. | D'Aloiso L | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16384843 |
Text-mined citations for rs377767415 ...
HelpRecord last updated May 27, 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.