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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 24, 2024
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:: RCV003487457.2

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)

Name:: Leukodystrophy
Synonyms:: Hypomyelinating leukodystrophy; Metachromatic leukodystrophy variant
Identifiers:: MONDO: MONDO:0019046; MedGen: C0023520; OMIM: PS312080; Human Phenotype Ontology: HP:0002415

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004232701	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 24, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004232701

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 24, 2024)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

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	curation

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

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004232701.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Glu1261Lys variant in POLR3A has been reported in 3 individuals with POLR3A related disorders (PMID: 23355746, 25339210, 28459997, Dinwiddie et al. 2012) and has been identified in 0.008% (2/24948) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs371703979). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 1184057) and has been interpreted as pathogenic by GeneReviews and as a variant of uncertain significance by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu1261Lys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015).

#	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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