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NM_000937.5(POLR2A):c.2207C>T (p.Thr736Met) AND Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 27, 2019
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000852291.1

Allele description [Variation Report for NM_000937.5(POLR2A):c.2207C>T (p.Thr736Met)]

NM_000937.5(POLR2A):c.2207C>T (p.Thr736Met)

Gene:
POLR2A:RNA polymerase II subunit A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000937.5(POLR2A):c.2207C>T (p.Thr736Met)
HGVS:
  • NC_000017.11:g.7501587C>T
  • NG_027747.1:g.22209C>T
  • NG_027747.2:g.22209C>T
  • NM_000937.5:c.2207C>T
  • NP_000928.1:p.Thr736Met
  • NC_000017.10:g.7404906C>T
  • NM_000937.4:c.2207C>T
Protein change:
T736M; THR736MET
Links:
OMIM: 180660.0004; dbSNP: rs1597798507
NCBI 1000 Genomes Browser:
rs1597798507
Molecular consequence:
  • NM_000937.5:c.2207C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities
Identifiers:
MONDO: MONDO:0032829; MedGen: C5231423; OMIM: 618603

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000994853OMIM
no assertion criteria provided
Pathogenic
(Sep 27, 2019) 		germlineliterature only

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.

Haijes HA, Koster MJE, Rehmann H, Li D, Hakonarson H, Cappuccio G, Hancarova M, Lehalle D, Reardon W, Schaefer GB, Lehman A, van de Laar IMBH, Tesselaar CD, Turner C, Goldenberg A, Patrier S, Thevenon J, Pinelli M, Brunetti-Pierri N, Prchalová D, Havlovicová M, Vlckova M, et al.

Am J Hum Genet. 2019 Aug 1;105(2):283-301. doi: 10.1016/j.ajhg.2019.06.016. Epub 2019 Jul 25.

PubMed [citation]
PMID:
31353023
PMCID:
PMC6699192

Details of each submission

From OMIM, SCV000994853.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a 4-year-old girl (patient 7) with profound form of neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB; 618603), Haijes et al. (2019) identified a de novo heterozygous c.2207C-T transition (c.2207C-T, NM_000937.4) in the POLR2A gene, resulting in a thr736-to-met (T736M) substitution at a conserved residue in the quay domain. In vitro studies of the corresponding mutation in yeast resulted in poor growth, suggesting decreased transcriptional fidelity, and expression of the mutation in HeLa cells resulted in decreased cell viability compared to controls. Interactome analysis indicated that the variant could still interact with other subunits to form the pol II complex. The authors suggested a dominant-negative effect.

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

Last Updated: Apr 23, 2022