NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter) AND not provided

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

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 25, 2023
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:: RCV000994469.26

Allele description

NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter)

Gene:

POLR3A:RNA polymerase III subunit A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.3

Genomic location:

Preferred name:

NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter)

Other names:

NM_007055.4(POLR3A):c.760C>T; p.Arg254Ter

HGVS:

NC_000010.11:g.78022270G>A
NG_029648.1:g.12271C>T
NM_007055.4:c.760C>TMANE SELECT
NP_008986.2:p.Arg254Ter
NC_000010.10:g.79782028G>A
NM_007055.3:c.760C>T

Protein change:

R254*; ARG254TER

Links:

OMIM: 614258.0020; dbSNP: rs141659018

NCBI 1000 Genomes Browser:

rs141659018

Molecular consequence:

NM_007055.4:c.760C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001148006	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Mar 1, 2018)	germline	clinical testing	Citation Link,
SCV001959515	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001972787	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002135625	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21855841, 25339210, 27612211, 30414627, 30450527, 28492532
SCV003930553	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 1, 2022)	germline	clinical testing	Citation Link

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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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.

Bernard G, Chouery E, Putorti ML, Tétreault M, Takanohashi A, Carosso G, Clément I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais B.

Am J Hum Genet. 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014. Erratum in: Am J Hum Genet. 2012 Nov 2;91(5):972.

PubMed [citation]

PMID:: 21855841
PMCID:: PMC3169829

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 (6)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001148006.23

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959515.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001972787.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002135625.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 617894). This premature translational stop signal has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30414627, 30450527). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs141659018, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg254*) in the POLR3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLR3A are known to be pathogenic (PMID: 21855841, 25339210, 27612211, 30414627, 30450527).

#	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 GeneDx, SCV003930553.1

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

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 30414627, 30450527)

#	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: Jun 17, 2024

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