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NM_014233.4(UBTF):c.628G>A (p.Glu210Lys) AND Rare syndromic intellectual disability

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 4, 2020
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:
RCV001195293.4

Allele description [Variation Report for NM_014233.4(UBTF):c.628G>A (p.Glu210Lys)]

NM_014233.4(UBTF):c.628G>A (p.Glu210Lys)

Genes:
ATXN7L3-AS1:ATXN7L3 antisense RNA 1 [Gene - HGNC]
UBTF:upstream binding transcription factor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_014233.4(UBTF):c.628G>A (p.Glu210Lys)
Other names:
NM_001076683.1:c.628G>A(p.Glu210Lys); NM_001076684.2:c.628G>A(p.Glu210Lys); NM_014233.3:c.628G>A(p.Glu210Lys)
HGVS:
  • NC_000017.11:g.44212851C>T
  • NG_029864.1:g.13776G>A
  • NM_001076683.2:c.628G>A
  • NM_001076684.3:c.628G>A
  • NM_014233.4:c.628G>AMANE SELECT
  • NP_001070151.1:p.Glu210Lys
  • NP_001070152.1:p.Glu210Lys
  • NP_055048.1:p.Glu210Lys
  • NC_000017.10:g.42290219C>T
  • NM_014233.2:c.628G>A
  • NM_014233.3:c.628G>A
  • NM_014233.4(UBTF):c.628G>AMANE SELECT
  • NR_045058.2:n.799G>A
  • p.Glu210Lys
Protein change:
E210K; GLU210LYS
Links:
OMIM: 600673.0001; dbSNP: rs1555582065
NCBI 1000 Genomes Browser:
rs1555582065
Molecular consequence:
  • NM_001076683.2:c.628G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001076684.3:c.628G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014233.4:c.628G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_045058.2:n.799G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
  • protein gain of function [Variation Ontology: 0040]
  • variation affecting protein function [Variation Ontology: 0003]
Observations:
1

Condition(s)

Name:
Rare syndromic intellectual disability
Identifiers:
MedGen: C5681780; Orphanet: 102369

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001365605Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(Mar 4, 2020) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown11not providednot providednot providedclinical testing

Citations

PubMed

A recurrent de novo missense mutation in UBTF causes developmental neuroregression.

Toro C, Hori RT, Malicdan MCV, Tifft CJ, Goldstein A, Gahl WA, Adams DR, Fauni HB, Wolfe LA, Xiao J, Khan MM, Tian J, Hope KA, Reiter LT, Tremblay MG, Moss T, Franks AL, Balak C; C4RCD Research Group., LeDoux MS.

Hum Mol Genet. 2018 Feb 15;27(4):691-705. doi: 10.1093/hmg/ddx435. Erratum in: Hum Mol Genet. 2018 Apr 1;27(7):1310. doi: 10.1093/hmg/ddy049.

PubMed [citation]
PMID:
29300972
PMCID:
PMC5886272

UBTF Mutation Causes Complex Phenotype of Neurodegeneration and Severe Epilepsy in Childhood.

Sedláčková L, Laššuthová P, Štěrbová K, Haberlová J, Vyhnálková E, Neupauerová J, Staněk D, Šedivá M, Kršek P, Seeman P.

Neuropediatrics. 2019 Feb;50(1):57-60. doi: 10.1055/s-0038-1676288. Epub 2018 Dec 5.

PubMed [citation]
PMID:
30517966
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365605.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.Glu210Lys variant in UBTF has been reported as a de novo occurrence, with maternity and paternity confirmed, in at least 10 individuals with clinical features of neurodegeneration in childhood (Edvardson et al 2017; Kosmicki et al 2017; Sedlackova et al 2018; Toro et al 2018; Bastos et al 2020). This variant has been reported in ClinVar (Variation ID: 437909) and was absent from large population studies. In vitro functional studies provide evidence that the p.Glu210Lys variant impacts protein function (PMID: 28777933, 29300972). However, these types of assays may not accurately represent biological function. Additionally, computational prediction tools and conservation analysis suggest that the p.Glu210Lys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for neurodegeneration in childhood in an autosomal dominant manner based upon de novo inheritance in multiple cases and absence from controls. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM2, PS3_Moderate, PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not provided1not provided

Last Updated: Jun 23, 2024