NM_030973.4(MED25):c.1966C>A (p.Pro656Thr) AND Charcot-Marie-Tooth disease type 2

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 12, 2022
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:: RCV000532947.14

Allele description

NM_030973.4(MED25):c.1966C>A (p.Pro656Thr)

Gene:

MED25:mediator complex subunit 25 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_030973.4(MED25):c.1966C>A (p.Pro656Thr)

HGVS:

NC_000019.10:g.49836226C>A
NG_017091.1:g.22948C>A
NM_001378355.1:c.1966C>A
NM_030973.4:c.1966C>AMANE SELECT
NP_001365284.1:p.Pro656Thr
NP_112235.2:p.Pro656Thr
NP_112235.2:p.Pro656Thr
LRG_368t1:c.1966C>A
LRG_368:g.22948C>A
LRG_368p1:p.Pro656Thr
NC_000019.9:g.50339483C>A
NM_030973.3:c.1966C>A

Protein change:

P656T

Links:

dbSNP: rs199761611

NCBI 1000 Genomes Browser:

rs199761611

Molecular consequence:

NM_001378355.1:c.1966C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_030973.4:c.1966C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 2
Synonyms:: Charcot-Marie-Tooth, Type 2
Identifiers:: MONDO: MONDO:0018993; MedGen: C0270914

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000414331	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Uncertain significance (Jun 14, 2016)	germline	clinical testing	ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000657764	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 12, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26257172, 30039206, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000414331

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification 20161018)

Uncertain significance
(Jun 14, 2016)

germline

clinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000657764

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 12, 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

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.

Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L, Ozes B, Karaca E, Jhangiani SN, Bainbridge MN, Lawson KS, Pehlivan D, Okamoto Y, Withers M, Mancias P, Slavotinek A, Reitnauer PJ, Goksungur MT, Shy M, Crawford TO, Koenig M, Willer J, et al.

Cell Rep. 2015 Aug 18;12(7):1169-83. doi: 10.1016/j.celrep.2015.07.023. Epub 2015 Aug 6.

PubMed [citation]

PMID:: 26257172
PMCID:: PMC4545408

The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.

Leal A, Bogantes-Ledezma S, Ekici AB, Uebe S, Thiel CT, Sticht H, Berghoff M, Berghoff C, Morera B, Meisterernst M, Reis A.

Neurogenetics. 2018 Dec;19(4):215-225. doi: 10.1007/s10048-018-0555-7. Epub 2018 Jul 24.

PubMed [citation]

PMID:: 30039206
PMCID:: PMC6280876

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000414331.2

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

#	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 Invitae, SCV000657764.8

#	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 proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 656 of the MED25 protein (p.Pro656Thr). This variant is present in population databases (rs199761611, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 26257172, 30039206). ClinVar contains an entry for this variant (Variation ID: 329887). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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: Aug 4, 2024

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