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NM_007055.4(POLR3A):c.2707G>A (p.Gly903Arg) 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:
RCV003488780.2

Allele description [Variation Report for NM_007055.4(POLR3A):c.2707G>A (p.Gly903Arg)]

NM_007055.4(POLR3A):c.2707G>A (p.Gly903Arg)

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.2707G>A (p.Gly903Arg)
Other names:
NM_007055.4(POLR3A):c.2707G>A; p.Gly903Arg
HGVS:
  • NC_000010.11:g.77993277C>T
  • NG_029648.1:g.41264G>A
  • NM_007055.4:c.2707G>AMANE SELECT
  • NP_008986.2:p.Gly903Arg
  • NC_000010.10:g.79753035C>T
  • NM_007055.3:c.2707G>A
Protein change:
G903R
Links:
dbSNP: rs1399429058
NCBI 1000 Genomes Browser:
rs1399429058
Molecular consequence:
  • NM_007055.4:c.2707G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004232667Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 24, 2024) 		germlinecuration

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

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, SCV004232667.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The p.Gly903Arg variant in POLR3A has been reported in 1 individual with POLR3A-related disorders (PMID: 30323018), and has been identified in 0.002% (1/30616) of South Asian chromosomes chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1399429058). 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#: 549566) and has been interpreted as likely pathogenic by Tartaglia Lab (Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Gly903Arg variant is located in a region of POLR3A that is essential to protein folding and stability, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 30323018). In summary, the clinical significance of the p.Gly903Argvariant is uncertain. ACMG/AMP Criteria applied: PP3, PM1_supporting, PM2_supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 30, 2024