NM_020975.6(RET):c.1900T>G (p.Cys634Gly) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 2, 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:: RCV000182581.16

Allele description [Variation Report for NM_020975.6(RET):c.1900T>G (p.Cys634Gly)]

NM_020975.6(RET):c.1900T>G (p.Cys634Gly)

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.1900T>G (p.Cys634Gly)

Other names:

p.C634G:TGC>GGC

HGVS:

NC_000010.11:g.43114500T>G
NG_007489.1:g.42432T>G
NM_000323.2:c.1900T>G
NM_001355216.2:c.1138T>G
NM_001406743.1:c.1900T>G
NM_001406744.1:c.1900T>G
NM_001406759.1:c.1900T>G
NM_001406760.1:c.1900T>G
NM_001406761.1:c.1771T>G
NM_001406762.1:c.1771T>G
NM_001406764.1:c.1771T>G
NM_001406766.1:c.1612T>G
NM_001406767.1:c.1612T>G
NM_001406769.1:c.1504T>G
NM_001406770.1:c.1612T>G
NM_001406771.1:c.1462T>G
NM_001406772.1:c.1504T>G
NM_001406773.1:c.1462T>G
NM_001406774.1:c.1375T>G
NM_001406775.1:c.1174T>G
NM_001406776.1:c.1174T>G
NM_001406777.1:c.1174T>G
NM_001406778.1:c.1174T>G
NM_001406779.1:c.1003T>G
NM_001406780.1:c.1003T>G
NM_001406781.1:c.1003T>G
NM_001406782.1:c.1003T>G
NM_001406783.1:c.874T>G
NM_001406784.1:c.910T>G
NM_001406785.1:c.883T>G
NM_001406786.1:c.874T>G
NM_001406788.1:c.715T>G
NM_001406789.1:c.715T>G
NM_001406790.1:c.715T>G
NM_001406791.1:c.595T>G
NM_001406792.1:c.451T>G
NM_001406793.1:c.451T>G
NM_001406794.1:c.451T>G
NM_020629.2:c.1900T>G
NM_020630.7:c.1900T>G
NM_020975.6:c.1900T>GMANE SELECT
NP_000314.1:p.Cys634Gly
NP_001342145.1:p.Cys380Gly
NP_001342145.1:p.Cys380Gly
NP_001393672.1:p.Cys634Gly
NP_001393673.1:p.Cys634Gly
NP_001393688.1:p.Cys634Gly
NP_001393689.1:p.Cys634Gly
NP_001393690.1:p.Cys591Gly
NP_001393691.1:p.Cys591Gly
NP_001393693.1:p.Cys591Gly
NP_001393695.1:p.Cys538Gly
NP_001393696.1:p.Cys538Gly
NP_001393698.1:p.Cys502Gly
NP_001393699.1:p.Cys538Gly
NP_001393700.1:p.Cys488Gly
NP_001393701.1:p.Cys502Gly
NP_001393702.1:p.Cys488Gly
NP_001393703.1:p.Cys459Gly
NP_001393704.1:p.Cys392Gly
NP_001393705.1:p.Cys392Gly
NP_001393706.1:p.Cys392Gly
NP_001393707.1:p.Cys392Gly
NP_001393708.1:p.Cys335Gly
NP_001393709.1:p.Cys335Gly
NP_001393710.1:p.Cys335Gly
NP_001393711.1:p.Cys335Gly
NP_001393712.1:p.Cys292Gly
NP_001393713.1:p.Cys304Gly
NP_001393714.1:p.Cys295Gly
NP_001393715.1:p.Cys292Gly
NP_001393717.1:p.Cys239Gly
NP_001393718.1:p.Cys239Gly
NP_001393719.1:p.Cys239Gly
NP_001393720.1:p.Cys199Gly
NP_001393721.1:p.Cys151Gly
NP_001393722.1:p.Cys151Gly
NP_001393723.1:p.Cys151Gly
NP_065680.1:p.Cys634Gly
NP_065681.1:p.Cys634Gly
NP_065681.1:p.Cys634Gly
NP_065681.1:p.Cys634Gly
NP_066124.1:p.Cys634Gly
NP_066124.1:p.Cys634Gly
LRG_518t1:c.1900T>G
LRG_518t2:c.1900T>G
LRG_518:g.42432T>G
LRG_518p1:p.Cys634Gly
LRG_518p2:p.Cys634Gly
NC_000010.10:g.43609948T>G
NM_001355216.1:c.1138T>G
NM_020630.4:c.1900T>G
NM_020630.6:c.1900T>G
NM_020975.4:c.1900T>G
P07949:p.Cys634Gly

Protein change:

C151G; CYS634GLY

Links:

UniProtKB: P07949#VAR_006323; OMIM: 164761.0003; dbSNP: rs75076352

NCBI 1000 Genomes Browser:

rs75076352

Molecular consequence:

NM_000323.2:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1138T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1771T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1771T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1771T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.1612T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.1612T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1504T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.1612T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1462T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1504T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1462T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1375T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.874T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.910T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.883T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.874T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.715T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.715T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.715T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.595T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.451T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.451T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.451T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Mus musculus N-terminal EF-hand calcium binding protein 3 (Necab3), t...
PREDICTED: Mus musculus N-terminal EF-hand calcium binding protein 3 (Necab3), transcript variant X8, mRNA
gi|1907142097|ref|XM_030251902.2|

Nucleotide
Homo sapiens carnitine palmitoyltransferase 2 (CPT2), transcript variant 1, mRNA
Homo sapiens carnitine palmitoyltransferase 2 (CPT2), transcript variant 1, mRNA
gi|169790951|ref|NM_000098.2|

Nucleotide
LOC132409794 [Mus musculus]
LOC132409794 [Mus musculus]
Gene ID:132409794

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000234933	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 21, 2021)	germline	clinical testing	Citation Link,
SCV000605032	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jan 3, 2018)	germline	clinical testing	Citation Link,
SCV001144498	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 5, 2018)	germline	clinical testing	PubMed (21) [See all records that cite these PMIDs] 9950371, 30392857, 8099202, 21765987, 7915166, 9111993, 19201392, 18062802, 9467562, 20516206, 12000816, 12150334, 8797874, 9230192, 11238493, 7907913, 16314641, 16868135, 18063059, 29549836, 26467025
SCV001449636	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 15, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005198056	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	10	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain.

Sánchez B, Robledo M, Biarnes J, Sáez ME, Volpini V, Benítez J, Navarro E, Ruiz A, Antiñolo G, Borrego S.

J Med Genet. 1999 Jan;36(1):68-70.

PubMed [citation]

PMID:: 9950371
PMCID:: PMC1762956

Genetic characterization of medullary thyroid cancer in childhood survivors of the Chernobyl accident.

Fisher SB, Cote GJ, Bui-Griffith JH, Lu W, Tang X, Hai T, Fisher KE, Williams MD, Wistuba II, Waguespack SG, Dorman CM, Ludwig MS, Graham PH, Perrier ND, Lee JE, Grubbs EG.

Surgery. 2019 Jan;165(1):58-63. doi: 10.1016/j.surg.2018.08.029. Epub 2018 Nov 2.

PubMed [citation]

PMID:: 30392857

See all PubMed Citations (22)

Details of each submission

From GeneDx, SCV000234933.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24466223, 26267327, 30763276, 27349013, 28605116, 7907913, 12000816, 26071011, 8825918, 23416954, 9467562, 8981969, 12788868, 9174404, 18063059, 19201392, 9111993, 26758973, 28946813, 27864651, 29420094, 31510104, 19258401, 12150334, 18062802, 30392857, 8099202, 7915166, 7595170, 8557249, 21765987, 14633923)

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000605032.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The RET c.1900T>G;p.Cys634Gly variant (rs75076352) has been published in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) and at least one individual with pheochromocytoma (American Thyroid Association Guidelines Task Force 2009, Hedayati 2011, Neumann 2002, Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13908), but is not listed in the Genome Aggregation Database. The cysteine at codon 634 is conserved across a variety of species and computational programs (PolyPhen2, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. References: American Thyroid Association Guidelines Task Force. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 19(6):565-612. Hedayati M et al. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011:264248. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 346(19):1459-66. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.

#	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 Athena Diagnostics, SCV001144498.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (21)

Description

Located at a critical residue of the protein. Not found in the total gnomAD dataset, and the data is high quality (0/278388 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Co-segregation with disease is reported.

#	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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449636.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		10	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198056.1

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

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

Last Updated: Sep 29, 2024

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