ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.3184T>C (p.Tyr1062His)
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.3184T>C (p.Tyr1062His)
Variation ID: 823117 Accession: VCV000823117.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43126719 (GRCh38) [ NCBI UCSC ] 10: 43622167 (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 Mar 16, 2020 Apr 20, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.3184T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Tyr1062His missense NM_000323.2:c.3184T>C NP_000314.1:p.Tyr1062His missense NM_001355216.2:c.2422T>C NP_001342145.1:p.Tyr808His missense NM_001406743.1:c.3184T>C NP_001393672.1:p.Tyr1062His missense NM_001406744.1:c.3184T>C NP_001393673.1:p.Tyr1062His missense NM_001406761.1:c.3055T>C NP_001393690.1:p.Tyr1019His missense NM_001406762.1:c.3055T>C NP_001393691.1:p.Tyr1019His missense NM_001406763.1:c.3049T>C NP_001393692.1:p.Tyr1017His missense NM_001406764.1:c.3055T>C NP_001393693.1:p.Tyr1019His missense NM_001406765.1:c.3049T>C NP_001393694.1:p.Tyr1017His missense NM_001406766.1:c.2896T>C NP_001393695.1:p.Tyr966His missense NM_001406767.1:c.2896T>C NP_001393696.1:p.Tyr966His missense NM_001406768.1:c.2920T>C NP_001393697.1:p.Tyr974His missense NM_001406769.1:c.2788T>C NP_001393698.1:p.Tyr930His missense NM_001406770.1:c.2896T>C NP_001393699.1:p.Tyr966His missense NM_001406771.1:c.2746T>C NP_001393700.1:p.Tyr916His missense NM_001406772.1:c.2788T>C NP_001393701.1:p.Tyr930His missense NM_001406773.1:c.2746T>C NP_001393702.1:p.Tyr916His missense NM_001406774.1:c.2659T>C NP_001393703.1:p.Tyr887His missense NM_001406775.1:c.2458T>C NP_001393704.1:p.Tyr820His missense NM_001406776.1:c.2458T>C NP_001393705.1:p.Tyr820His missense NM_001406778.1:c.2458T>C NP_001393707.1:p.Tyr820His missense NM_001406779.1:c.2287T>C NP_001393708.1:p.Tyr763His missense NM_001406780.1:c.2287T>C NP_001393709.1:p.Tyr763His missense NM_001406781.1:c.2287T>C NP_001393710.1:p.Tyr763His missense NM_001406782.1:c.2287T>C NP_001393711.1:p.Tyr763His missense NM_001406783.1:c.2158T>C NP_001393712.1:p.Tyr720His missense NM_001406784.1:c.2194T>C NP_001393713.1:p.Tyr732His missense NM_001406785.1:c.2167T>C NP_001393714.1:p.Tyr723His missense NM_001406786.1:c.2158T>C NP_001393715.1:p.Tyr720His missense NM_001406787.1:c.2152T>C NP_001393716.1:p.Tyr718His missense NM_001406788.1:c.1999T>C NP_001393717.1:p.Tyr667His missense NM_001406789.1:c.1999T>C NP_001393718.1:p.Tyr667His missense NM_001406790.1:c.1999T>C NP_001393719.1:p.Tyr667His missense NM_001406791.1:c.1879T>C NP_001393720.1:p.Tyr627His missense NM_001406792.1:c.1735T>C NP_001393721.1:p.Tyr579His missense NM_001406794.1:c.1735T>C NP_001393723.1:p.Tyr579His missense NM_020629.2:c.3184T>C NP_065680.1:p.Tyr1062His missense NM_020630.7:c.3184T>C NP_065681.1:p.Tyr1062His missense NC_000010.11:g.43126719T>C NC_000010.10:g.43622167T>C NG_007489.1:g.54651T>C LRG_518:g.54651T>C LRG_518t1:c.3184T>C LRG_518p1:p.Tyr1062His LRG_518t2:c.3184T>C LRG_518p2:p.Tyr1062His - Protein change
- Y1062H, Y808H, Y1017H, Y718H, Y723H, Y930H, Y974H, Y579H, Y732H, Y763H, Y916H, Y1019H, Y627H, Y667H, Y887H, Y720H, Y820H, Y966H
- Other names
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- Canonical SPDI
- NC_000010.11:43126718:T: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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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
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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 |
3446 | 3566 |
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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Dec 20, 2021 | RCV001019049.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV001247987.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 15, 2021 | RCV002479216.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV003962995.1 |
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
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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
(Dec 20, 2021)
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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: SCV001180356.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The p.Y1062H variant (also known as c.3184T>C), located in coding exon 19 of the RET gene, results from a T to C substitution at nucleotide … (more)
The p.Y1062H variant (also known as c.3184T>C), located in coding exon 19 of the RET gene, results from a T to C substitution at nucleotide position 3184. The tyrosine at codon 1062 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for p.Y1062H is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 15, 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 IIB Pheochromocytoma MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002777981.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Dec 19, 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: SCV001421445.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1062 of the RET protein (p.Tyr1062His). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1062 of the RET protein (p.Tyr1062His). This variant is present in population databases (rs138010639, 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: 823117). 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. 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
(Nov 21, 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: SCV004779780.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The RET c.3184T>C variant is predicted to result in the amino acid substitution p.Tyr1062His. This variant was reported in an individual presenting with intractable seizures … (more)
The RET c.3184T>C variant is predicted to result in the amino acid substitution p.Tyr1062His. This variant was reported in an individual presenting with intractable seizures (Supplemental Table 1, Chetruengchai et al 2022. PubMed ID: 34621001). A different variant impacting the same amino acid residue (p.Tyr1062Cys) has been reported in individuals with Hirschsprung disease (Wu et al. 2005. PubMed ID: 15834508). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. 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
(Jul 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004838728.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces tyrosine with histidine at codon 1062 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces tyrosine with histidine at codon 1062 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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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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Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. | So MT | PloS one | 2011 | PMID: 22174939 |
Text-mined citations for rs138010639 ...
HelpRecord last updated Apr 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.