NM_007055.4(POLR3A):c.3781G>A (p.Glu1261Lys) AND Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 24, 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:: RCV001542014.3

Allele description [Variation Report for NM_007055.4(POLR3A):c.3781G>A (p.Glu1261Lys)]

NM_007055.4(POLR3A):c.3781G>A (p.Glu1261Lys)

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.3781G>A (p.Glu1261Lys)

Other names:

NM_007055.4(POLR3A):c.3781G>A; p.Glu1261Lys

HGVS:

NC_000010.11:g.77981538C>T
NG_029648.1:g.53003G>A
NM_007055.4:c.3781G>AMANE SELECT
NP_008986.2:p.Glu1261Lys
NC_000010.10:g.79741296C>T
NM_007055.3:c.3781G>A

Protein change:

E1261K

Links:

dbSNP: rs371703979

NCBI 1000 Genomes Browser:

rs371703979

Molecular consequence:

NM_007055.4:c.3781G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Synonyms:: LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM; LEUKOENCEPHALOPATHY, HYPOMYELINATING, WITH ATAXIA AND DELAYED DENTITION; ATAXIA, DELAYED DENTITION, AND HYPOMYELINATION; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011897; MedGen: C2676243; Orphanet: 137639; Orphanet: 447893; Orphanet: 447896; Orphanet: 77295; Orphanet: 88637; OMIM: 607694

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001760653	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 25339210, 22855961
SCV005187410	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 24, 2020)	maternal, unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23355746, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001760653

GeneReviews

no classification provided

not provided

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV005187410

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 24, 2020)

maternal, unknown

clinical testing

PubMed (2)
[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	literature only
not provided	maternal	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	no	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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

POLR3-Related Leukodystrophy..

Bernard G, Vanderver A.

2012 Aug 2 [updated 2017 May 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 22855961

See all PubMed Citations (4)

Details of each submission

From GeneReviews, SCV001760653.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	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 Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV005187410.1

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

Description

This missense variant (c.3781G>A, p.Glu1261Lys) has been observed at extremely low frequency in population databases (gnomAD) and has been reported in the literature (PMID 23355746). Variant prediction programs suggest a deleterious effect, although no functional studies have been published. It was found in trans with another likely pathogenic variant (c.1160C>G, p.Ala387Gly).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	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
3	unknown	no	1	blood	not provided	(GTR000331877.3)	1	not provided	not provided	not provided

Last Updated: Nov 18, 2024

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