ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.341G>A (p.Arg114His)
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.341G>A (p.Arg114His)
Variation ID: 13947 Accession: VCV000013947.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43102345 (GRCh38) [ NCBI UCSC ] 10: 43597793 (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 Jun 9, 2014 Oct 20, 2024 Jan 30, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.341G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Arg114His missense NM_000323.2:c.341G>A NP_000314.1:p.Arg114His missense NM_001406743.1:c.341G>A NP_001393672.1:p.Arg114His missense NM_001406744.1:c.341G>A NP_001393673.1:p.Arg114His missense NM_001406759.1:c.341G>A NP_001393688.1:p.Arg114His missense NM_001406760.1:c.341G>A NP_001393689.1:p.Arg114His missense NM_001406763.1:c.341G>A NP_001393692.1:p.Arg114His missense NM_001406765.1:c.341G>A NP_001393694.1:p.Arg114His missense NM_001406769.1:c.341G>A NP_001393698.1:p.Arg114His missense NM_001406771.1:c.341G>A NP_001393700.1:p.Arg114His missense NM_001406772.1:c.341G>A NP_001393701.1:p.Arg114His missense NM_001406773.1:c.341G>A NP_001393702.1:p.Arg114His missense NM_001406779.1:c.341G>A NP_001393708.1:p.Arg114His missense NM_001406780.1:c.341G>A NP_001393709.1:p.Arg114His missense NM_001406781.1:c.341G>A NP_001393710.1:p.Arg114His missense NM_001406782.1:c.341G>A NP_001393711.1:p.Arg114His missense NM_001406785.1:c.341G>A NP_001393714.1:p.Arg114His missense NM_001406787.1:c.341G>A NP_001393716.1:p.Arg114His missense NM_020629.2:c.341G>A NP_065680.1:p.Arg114His missense NM_020630.7:c.341G>A NP_065681.1:p.Arg114His missense NC_000010.11:g.43102345G>A NC_000010.10:g.43597793G>A NG_007489.1:g.30277G>A LRG_518:g.30277G>A LRG_518t1:c.341G>A LRG_518p1:p.Arg114His LRG_518t2:c.341G>A LRG_518p2:p.Arg114His P07949:p.Arg114His - Protein change
- R114H
- Other names
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- Canonical SPDI
- NC_000010.11:43102344: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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0.00140 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00036
The Genome Aggregation Database (gnomAD), exomes 0.00079
Exome Aggregation Consortium (ExAC) 0.00088
1000 Genomes Project 30x 0.00109
1000 Genomes Project 0.00140
- 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 | ||
|---|---|---|---|---|---|---|
| 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 |
3598 | 3720 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
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Apr 1, 2002 | RCV000014974.35 | |
| Benign (2) |
criteria provided, single submitter
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Jan 5, 2017 | RCV000121988.11 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
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Apr 28, 2020 | RCV000163885.13 | |
| Benign (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV000198261.21 | |
| Benign (1) |
criteria provided, single submitter
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Mar 18, 2016 | RCV000490359.9 | |
| Benign (1) |
criteria provided, single submitter
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Nov 21, 2018 | RCV000755684.10 | |
| Likely benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001106778.12 | |
| Benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001107412.12 | |
| Benign (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV001106779.12 | |
| Likely benign (1) |
criteria provided, single submitter
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Aug 1, 2023 | RCV003389668.10 | |
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RET-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Apr 5, 2024 | RCV004739309.1 |
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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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Benign
(Jan 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000521034.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267473.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Benign
(Nov 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883097.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
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Likely benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Renal hypodysplasia/aplasia 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001263874.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001263875.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001264555.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
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Benign
(Apr 28, 2020)
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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: SCV002527911.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Jan 30, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000252850.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
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Benign
(Nov 09, 2015)
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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: SCV000214475.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500426.17
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Comment:
RET: BP4, BS1
Number of individuals with the variant: 1
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Uncertain significance
(Apr 01, 2002)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035230.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 21, 2021 |
Comment on evidence:
This variant, formerly titled CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, has been reclassified based on its allele frequency in the gnomAD database (v.2.1.1) (Hamosh, 2021). In a … (more)
This variant, formerly titled CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, has been reclassified based on its allele frequency in the gnomAD database (v.2.1.1) (Hamosh, 2021). In a patient with congenital central hypoventilation syndrome (CCHS; 209880), an 8-year-old girl, Kanai et al. (2002) found a 341G-A transition in exon 3 of the RET gene resulting in an arg114-to-his (R114H) amino acid substitution. The mutation was inherited from her healthy father and was absent in 50 healthy Japanese controls. The patient required home ventilation therapy only during sleep and presented normal psychomotor development. She was born at term and showed hypoventilation and/or apnea soon after birth, especially during sleep, and required endotracheal intubation and mechanical ventilation within a few hours after birth. Respiratory function tests performed during sleep showed extremely low or no response to hypercapnia. There was no increase in minute ventilation, even when blood carbon dioxide levels increased, although results of the respiratory function test during the awake state were normal. Screening tests for neuroblastoma were negative and symptoms suggesting Hirschsprung disease (142623) or tumors of neural crest origin were not detected. The patient had very mild constipation (treatment was not needed), strabismus, and incomplete right bundle branch block. Kanai (2002) claimed that this was the first report of a RET gene mutation in a patient with isolated CCHS. Hamosh (2021) noted that the R114H variant has a frequency of 0.01022 among East Asians (204/19,952) and was identified in one homozygote in gnomAD. This is too high a frequency to account for a severe pediatric disorder. (less)
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Uncertain significance
(Apr 05, 2024)
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no assertion criteria provided
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: SCV005349601.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The RET c.341G>A variant is predicted to result in the amino acid substitution p.Arg114His. This variant has been described as a recurrent variant in individuals … (more)
The RET c.341G>A variant is predicted to result in the amino acid substitution p.Arg114His. This variant has been described as a recurrent variant in individuals with Hirschprung disease and Chinese ancestry, although it has also been found in unaffected parents (Garcia-Barceló et al. 2004. PubMed ID: 14633923; Cornes et al. 2010. PubMed ID: 20532249). This variant has also been described in presumably healthy controls and is present in population databases in up to 1.0% individuals, with East Asian descent being the most prevalent (Bodian et al. 2014. PubMed ID: 24728327; Olfson et al. 2015. PubMed ID: 26332594; http://gnomad.broadinstitute.org/variant/10-43597793-G-A). This variant change resides within the Tyrosine-protein kinase, Ret receptor domain. In vitro functional characterization of this variant suggests that it does not result in loss of function, as would be expected for a pathogenic variant in Hirschsprung disease (Kjaer et al. 2010. PubMed ID: 20473317). These observations suggest that the c.314A>G (p.Arg114His) variant is possibly benign or a risk factor for Hirschsprung disease. Although we suspect that this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic information. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000086199.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| Screening of the RET gene of Vietnamese Hirschsprung patients identifies 2 novel missense mutations. | Ngo DN | Journal of pediatric surgery | 2012 | PMID: 23084198 |
| RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. | So MT | PloS one | 2011 | PMID: 22174939 |
| Haplotype analysis reveals a possible founder effect of RET mutation R114H for Hirschsprung's disease in the Chinese population. | Cornes BK | PloS one | 2010 | PMID: 20532249 |
| Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations. | Kjaer S | Nature structural & molecular biology | 2010 | PMID: 20473317 |
| 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 |
| Congenital central hypoventilation syndrome: a novel mutation of the RET gene in an isolated case. | Kanai M | The Tohoku journal of experimental medicine | 2002 | PMID: 12086152 |
| Hamosh, A. Personal Communication. 2021. Baltimore, Md. | - | - | - | - |
| Kanai, M. Personal Communication. 2002. Yamagata, Japan | - | - | - | - |
Text-mined citations for rs76397662 ...
HelpRecord last updated Nov 25, 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.