NM_018082.6(POLR3B):c.2084-6A>G AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 17, 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:: RCV000484819.15

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]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568202	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 10, 2022)	germline	clinical testing	Citation Link,
SCV001446583	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002011556	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002164863	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25339210, 23355746, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.

Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais B, Bugiani M, Sistermans E, Catsman-Berrevoets C, Kros JM, Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap MS, Bernard G; 4H Research Group.

Neurology. 2014 Nov 18;83(21):1898-905. doi: 10.1212/WNL.0000000000001002. Epub 2014 Oct 22.

PubMed [citation]

PMID:: 25339210
PMCID:: PMC4248461

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000568202.6

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

Description

RT-PCR studies of c.2084-6A>G indicate that it creates a cryptic splice acceptor site, leading to a frameshift and a premature stop codon at position 5 of the new reading frame (Daoud et al., 2013); This variant is associated with the following publications: (PMID: 27029625, 23355746, 25339210, 26478204, 31980526)

#	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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446583.2

#	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	1	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002011556.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002164863.4

#	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 falls in intron 19 of the POLR3B gene. It does not directly change the encoded amino acid sequence of the POLR3B protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs747912710, gnomAD 0.02%). This variant has been observed in individuals with leukodystrophy (PMID: 23355746, 25339210). ClinVar contains an entry for this variant (Variation ID: 419962). Studies have shown that this variant results in an abnormal splicing event, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23355746). For these reasons, this variant has been classified as Pathogenic.

#	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: May 16, 2025

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