NM_007055.4(POLR3A):c.3781G>A (p.Glu1261Lys) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 30, 2021
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:: RCV002032525.3

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]

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
SCV002312967	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 30, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23355746, 25339210, 28459997, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002312967

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 30, 2021)

germline

clinical testing

PubMed (4)
[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

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

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002312967.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1261 of the POLR3A protein (p.Glu1261Lys). This variant is present in population databases (rs371703979, gnomAD 0.008%). This missense change has been observed in individual(s) with hypomyelinating leukodystrophy and/or Leukodystrophy (PMID: 23355746, 25339210, 28459997). ClinVar contains an entry for this variant (Variation ID: 1184057). 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: "Probably 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: Nov 18, 2024

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