NM_020975.6(RET):c.1424G>A (p.Arg475Gln) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000470554.13

Allele description [Variation Report for NM_020975.6(RET):c.1424G>A (p.Arg475Gln)]

NM_020975.6(RET):c.1424G>A (p.Arg475Gln)

Gene:

RET:ret proto-oncogene [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q11.21

Genomic location:

Preferred name:

NM_020975.6(RET):c.1424G>A (p.Arg475Gln)

HGVS:

NC_000010.11:g.43111367G>A
NG_007489.1:g.39299G>A
NM_000323.2:c.1424G>A
NM_001355216.2:c.662G>A
NM_001406743.1:c.1424G>A
NM_001406744.1:c.1424G>A
NM_001406759.1:c.1424G>A
NM_001406760.1:c.1424G>A
NM_001406761.1:c.1295G>A
NM_001406762.1:c.1295G>A
NM_001406763.1:c.1424G>A
NM_001406764.1:c.1295G>A
NM_001406765.1:c.1424G>A
NM_001406766.1:c.1136G>A
NM_001406767.1:c.1136G>A
NM_001406768.1:c.1295G>A
NM_001406769.1:c.1028G>A
NM_001406770.1:c.1136G>A
NM_001406771.1:c.986G>A
NM_001406772.1:c.1028G>A
NM_001406773.1:c.986G>A
NM_001406774.1:c.899G>A
NM_001406775.1:c.698G>A
NM_001406776.1:c.698G>A
NM_001406777.1:c.698G>A
NM_001406778.1:c.698G>A
NM_001406784.1:c.434G>A
NM_020629.2:c.1424G>A
NM_020630.7:c.1424G>A
NM_020975.6:c.1424G>AMANE SELECT
NP_000314.1:p.Arg475Gln
NP_001342145.1:p.Arg221Gln
NP_001342145.1:p.Arg221Gln
NP_001393672.1:p.Arg475Gln
NP_001393673.1:p.Arg475Gln
NP_001393688.1:p.Arg475Gln
NP_001393689.1:p.Arg475Gln
NP_001393690.1:p.Arg432Gln
NP_001393691.1:p.Arg432Gln
NP_001393692.1:p.Arg475Gln
NP_001393693.1:p.Arg432Gln
NP_001393694.1:p.Arg475Gln
NP_001393695.1:p.Arg379Gln
NP_001393696.1:p.Arg379Gln
NP_001393697.1:p.Arg432Gln
NP_001393698.1:p.Arg343Gln
NP_001393699.1:p.Arg379Gln
NP_001393700.1:p.Arg329Gln
NP_001393701.1:p.Arg343Gln
NP_001393702.1:p.Arg329Gln
NP_001393703.1:p.Arg300Gln
NP_001393704.1:p.Arg233Gln
NP_001393705.1:p.Arg233Gln
NP_001393706.1:p.Arg233Gln
NP_001393707.1:p.Arg233Gln
NP_001393713.1:p.Arg145Gln
NP_065680.1:p.Arg475Gln
NP_065681.1:p.Arg475Gln
NP_065681.1:p.Arg475Gln
NP_065681.1:p.Arg475Gln
NP_066124.1:p.Arg475Gln
NP_066124.1:p.Arg475Gln
LRG_518t1:c.1424G>A
LRG_518t2:c.1424G>A
LRG_518:g.39299G>A
LRG_518p1:p.Arg475Gln
LRG_518p2:p.Arg475Gln
NC_000010.10:g.43606815G>A
NM_001355216.1:c.662G>A
NM_020630.4:c.1424G>A
NM_020630.6:c.1424G>A
NM_020975.4:c.1424G>A
P07949:p.Arg475Gln

Protein change:

R145Q

Links:

UniProtKB: P07949#VAR_006305; dbSNP: rs138624658

NCBI 1000 Genomes Browser:

rs138624658

Molecular consequence:

NM_000323.2:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.662G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.1136G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.1136G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.1295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1028G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.1136G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.986G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1028G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.986G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.899G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.698G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.698G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.698G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.698G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.434G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple endocrine neoplasia, type 2 (MEN2)
Identifiers:: MONDO: MONDO:0019003; MedGen: C4048306

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000543838	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 4, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20473317, 28492532
SCV004821574	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20473317, 24728327, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543838

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 4, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004821574

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 5, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.

Kjaer S, Hanrahan S, Totty N, McDonald NQ.

Nat Struct Mol Biol. 2010 Jun;17(6):726-31. doi: 10.1038/nsmb.1808. Epub 2010 May 16.

PubMed [citation]

PMID:: 20473317

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543838.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 475 of the RET protein (p.Arg475Gln). This variant is present in population databases (rs138624658, gnomAD 0.007%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 20473317). ClinVar contains an entry for this variant (Variation ID: 135188). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004821574.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with glutamine at codon 475 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual with sporadic Hirschsprung disease (PMID: 20473317) and has also been identified in a healthy subject (PMID: 24728327) This variant has been identified in 3/251358 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: May 16, 2025

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