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NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter) AND Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 24, 2023
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:
RCV002533777.3

Allele description [Variation Report for NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter)]

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]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003761141Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jan 24, 2023) 		germlinecuration

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

Help

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, SCV003761141.1

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

Description

The p.Arg254Ter variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with POLR3A-related disorders (PMID: 30450527, 30414627) and has been identified in 0.01% (3/24970) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs141659018). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 617894) and has been interpreted as pathogenic or likely pathogenic by multiple laboratories. This nonsense variant leads to a premature termination codon at position 254, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive POLR3A-related disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3 (Richards 2015).

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

Last Updated: Oct 20, 2024