NM_017849.4(TMEM127):c.185C>G (p.Ser62Trp) AND Hereditary pheochromocytoma-paraganglioma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 18, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003031112.2

Allele description [Variation Report for NM_017849.4(TMEM127):c.185C>G (p.Ser62Trp)]

NM_017849.4(TMEM127):c.185C>G (p.Ser62Trp)

Gene:

TMEM127:transmembrane protein 127 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q11.2

Genomic location:

Preferred name:

NM_017849.4(TMEM127):c.185C>G (p.Ser62Trp)

HGVS:

NC_000002.12:g.96265197G>C
NG_027695.1:g.5817C>G
NM_001193304.3:c.185C>G
NM_017849.4:c.185C>GMANE SELECT
NP_001180233.1:p.Ser62Trp
NP_060319.1:p.Ser62Trp
NP_060319.1:p.Ser62Trp
LRG_528t1:c.185C>G
LRG_528:g.5817C>G
LRG_528p1:p.Ser62Trp
NC_000002.11:g.96930935G>C
NM_017849.3:c.185C>G

Protein change:

S62W

Molecular consequence:

NM_001193304.3:c.185C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_017849.4:c.185C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary pheochromocytoma-paraganglioma
Synonyms:: Hereditary Paraganglioma-Pheochromocytoma Syndromes; Hereditary Paragangliomas and Pheochromocytomas
Identifiers:: MONDO: MONDO:0017366; MedGen: C1708353

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003319288	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 18, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32575117, 33051659, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003319288

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 18, 2022)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional Characterization of TMEM127 Variants Reveals Novel Insights into Its Membrane Topology and Trafficking.

Flores SK, Deng Y, Cheng Z, Zhang X, Tao S, Saliba A, Chu I, Burnichon N, Gimenez-Roqueplo AP, Wang E, Aguiar RCT, Dahia PLM.

J Clin Endocrinol Metab. 2020 Sep 1;105(9). doi:pii: dgaa396. 10.1210/clinem/dgaa396.

PubMed [citation]

PMID:: 32575117
PMCID:: PMC7414969

Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update.

Armaiz-Pena G, Flores SK, Cheng ZM, Zhang X, Esquivel E, Poullard N, Vaidyanathan A, Liu Q, Michalek J, Santillan-Gomez AA, Liss M, Ahmadi S, Katselnik D, Maldonado E, Salgado SA, Jimenez C, Fishbein L, Hamidi O, Else T, Lechan R, Tischler AS, Benn DE, et al.

J Clin Endocrinol Metab. 2021 Jan 1;106(1):e350-e364. doi: 10.1210/clinem/dgaa741.

PubMed [citation]

PMID:: 33051659
PMCID:: PMC7765648

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003319288.2

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

Description

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 62 of the TMEM127 protein (p.Ser62Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pheochromocytoma (PMID: 32575117, 33051659). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TMEM127 function (PMID: 32575117, 33051659). 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

Last Updated: Feb 20, 2024

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