NM_018082.6(POLR3B):c.2084-6A>G AND Charcot-Marie-Tooth disease, demyelinating, IIA 1I

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 23, 2020
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:: RCV004691238.2

Allele description [Variation Report for NM_018082.6(POLR3B):c.2084-6A>G]

NM_018082.6(POLR3B):c.2084-6A>G

Gene:

POLR3B:RNA polymerase III subunit B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.3

Genomic location:

Preferred name:

NM_018082.6(POLR3B):c.2084-6A>G

HGVS:

NC_000012.12:g.106454496A>G
NG_031837.1:g.101839A>G
NM_001160708.2:c.1910-6A>G
NM_018082.6:c.2084-6A>GMANE SELECT
NC_000012.11:g.106848274A>G
NM_018082.5:c.2084-6A>G

Nucleotide change:

IVS19AS, -6, A-G

Links:

OMIM: 614366.0016; dbSNP: rs747912710

NCBI 1000 Genomes Browser:

rs747912710

Molecular consequence:

NM_001160708.2:c.1910-6A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_018082.6:c.2084-6A>G - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Charcot-Marie-Tooth disease, demyelinating, IIA 1I
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 1I; Charcot-Marie-Tooth disease, demyelinating, type 1I
Identifiers:: MONDO: MONDO:0030677; MedGen: C5676914; OMIM: 619742

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005187405	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 23, 2020)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23355746, 27029625, 25339210, 26478204, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005187405

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 23, 2020)

unknown

clinical testing

PubMed (5)
[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	unknown	yes	2	not provided	not provided	2	not provided	clinical testing

Citations

PubMed

Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.

Daoud H, Tétreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J, Synofzik M, Brais B, Stevens CA, Sanchez-Carpintero R, Goizet C, Naidu S, Vanderver A, Bernard G.

J Med Genet. 2013 Mar;50(3):194-7. doi: 10.1136/jmedgenet-2012-101357. Epub 2013 Jan 25.

PubMed [citation]

PMID:: 23355746

Diffuse hypomyelination is not obligate for POLR3-related disorders.

La Piana R, Cayami FK, Tran LT, Guerrero K, van Spaendonk R, Õunap K, Pajusalu S, Haack T, Wassmer E, Timmann D, Mierzewska H, Poll-Thé BT, Patel C, Cox H, Atik T, Onay H, Ozkınay F, Vanderver A, van der Knaap MS, Wolf NI, Bernard G.

Neurology. 2016 Apr 26;86(17):1622-6. doi: 10.1212/WNL.0000000000002612. Epub 2016 Mar 30.

PubMed [citation]

PMID:: 27029625
PMCID:: PMC4844237

See all PubMed Citations (5)

Details of each submission

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV005187405.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing (GTR000331877.3)	PubMed (5)
2	not provided	1	not provided	not provided	clinical testing (GTR000331877.3)	PubMed (5)

Description

This variant (c.2084-6G>A) has been observed at very low frequency in population databases (gnomAD) and has been reported in the literature (PMID 23355746, PMID 27029625, PMID. 25339210, PMID 26478204). Splice prediction programs suggest a deleterious effect on correct splicing and this is supoprted by RNA analysis (PMID 23355746). The change was found in an affected individual who is also heterozygous for another likely pathogenic varaint (c.1999G>A, p.Val667Met), although no parental studies were performed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	blood	not provided	(GTR000331877.3)	1	not provided	not provided	not provided
2	unknown	yes	1	blood	not provided	(GTR000331877.3)	1	not provided	not provided	not provided

Last Updated: Apr 13, 2025

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