ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.3191T>C (p.Met1064Thr)
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.3191T>C (p.Met1064Thr)
Variation ID: 161359 Accession: VCV000161359.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43128115 (GRCh38) [ NCBI UCSC ] 10: 43623563 (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 Dec 7, 2014 May 1, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.3191T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Met1064Thr missense NC_000010.11:g.43128115T>C NC_000010.10:g.43623563T>C NG_007489.1:g.56047T>C LRG_518:g.56047T>C LRG_518t1:c.3191T>C P07949:p.Met1064Thr - Protein change
- M1064T
- Other names
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- Canonical SPDI
- NC_000010.11:43128114: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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148784.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000557293.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2023 | RCV000569531.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 13, 2022 | RCV002505137.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 24, 2023 | RCV003462057.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 18, 2022 | RCV003480062.1 |
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
(Oct 24, 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: SCV004208641.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Oct 31, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527906.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RET c.3191T>C (p.M1064T) variant has been reported in heterozygosity in at least three individuals with Hirschsprung disease (PMID: 7581377, 22395866, 14633923, 27525386). This variant … (more)
The RET c.3191T>C (p.M1064T) variant has been reported in heterozygosity in at least three individuals with Hirschsprung disease (PMID: 7581377, 22395866, 14633923, 27525386). This variant has also been reported in at least one individual with medullary thyroid cancer (PMID: 27525386). It was observed in two members of a family affected with Hirschsprung disease; however, it was not found to fully segregate with disease as a third family member that carried this variant was unaffected (PMID: 7581377). A functional study demonstrated the normal transforming capacity, neuronal differentiation capability, or catalytic activity of the protein when co-transfected with a constitutively activated MEN2A form of RET (PMID: 9502784). However, a different functional study demonstrated a 30-40% reduction in binding affinity for the PTB domain of Shc at Y1064 and a 50% reduction in Shc phosphorylation versus wild type (PMID: 9047383). This variant was observed in 3/16256 chromosomes in the African/African American subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 161359). In silico tools suggest the impact of the variant on protein function is deleterious. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Apr 13, 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 2B Pheochromocytoma Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002814519.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Mar 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225232.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3
Number of individuals with the variant: 1
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Uncertain significance
(Jan 13, 2024)
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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: SCV000658476.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1064 of the RET protein (p.Met1064Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1064 of the RET protein (p.Met1064Thr). This variant is present in population databases (rs149513065, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of RET-related conditions (PMID: 7581377, 14633923, 27525386). ClinVar contains an entry for this variant (Variation ID: 161359). 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: 9047383, 9502784). 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
(Dec 13, 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: SCV004828166.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces methionine with threonine at codon 1064 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces methionine with threonine at codon 1064 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). Functional studies have reported conflicting evidence of this variant's impact on transforming and kinase activity (PMID: 9047383, 9502784). This variant has been reported in an individual affected with medullary thyroid cancer (PMID: 27525386) and individuals affected with Hirschsprung disease (PMID: 14633923, 22174939, 22395866). This variant has been identified in 4/251476 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: 6
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Uncertain significance
(Apr 04, 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: SCV000674853.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.M1064T variant (also known as c.3191T>C), located in coding exon 20 of the RET gene, results from a T to C substitution at nucleotide … (more)
The p.M1064T variant (also known as c.3191T>C), located in coding exon 20 of the RET gene, results from a T to C substitution at nucleotide position 3191. The methionine at codon 1064 is replaced by threonine, an amino acid with similar properties. This variant has previously been reported in individuals affected with Hirschsprung disease (So MT et al. PLoS ONE 2011 Dec; 6(12):e28986; Attié T et al. Hum. Mol. Genet. 1995 Aug; 4(8):1381-6; Jannot AS et al. Eur. J. Hum. Genet. 2012 Sep; 20(9):917-20; Garcia-Barceló M et al. Clin Chem, 2004 Jan;50:93-100), as well as medullary thyroid cancer and pheochromocytoma (Sherman S et al. Cancer 2016 Dec;122(24):3856-3864; Ambry internal data). However, this variant has been detected in multiple individuals with no reported features of RET-associated disease (Ambry internal data). Functional studies using co-transfection with a constitutively activated MEN2A form of RET have shown this variant has minimal biological effect (Pelet A et al. J. Clin. Invest. 1998 Mar; 101(6):1415-23). Another study evaluated the effects of this alteration on binding various domains of the adaptor protein Shc, and found that p.M1064T binds three domains equally well as wild-type; but demonstrates a 30-40% reduction in binding affinity for the PTB domain of Shc (JLorenzo MJ et al. Oncogene 1997 Feb; 14(7):763-71). 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 conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Hirschsprung disease
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190522.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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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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Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. | Sherman SI | Cancer | 2016 | PMID: 27525386 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach. | George Priya Doss C | Molecular bioSystems | 2014 | PMID: 24336963 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease. | Jannot AS | European journal of human genetics : EJHG | 2012 | PMID: 22395866 |
RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. | So MT | PloS one | 2011 | PMID: 22174939 |
Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. | Garcia-Barceló M | Clinical chemistry | 2004 | PMID: 14633923 |
Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease. | Pelet A | The Journal of clinical investigation | 1998 | PMID: 9502784 |
Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. | Eng C | Human mutation | 1997 | PMID: 9067749 |
RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2. | Lorenzo MJ | Oncogene | 1997 | PMID: 9047383 |
Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. | Attié T | Human molecular genetics | 1995 | PMID: 7581377 |
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Text-mined citations for rs149513065 ...
HelpRecord last updated May 12, 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.