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NM_181721.3(FOXR1):c.838A>T (p.Met280Leu) AND not provided

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 3, 2023
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:
RCV003319296.1

Allele description [Variation Report for NM_181721.3(FOXR1):c.838A>T (p.Met280Leu)]

NM_181721.3(FOXR1):c.838A>T (p.Met280Leu)

Gene:
FOXR1:forkhead box R1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q23.3
Genomic location:
Preferred name:
NM_181721.3(FOXR1):c.838A>T (p.Met280Leu)
Other names:
M280L
HGVS:
  • NC_000011.10:g.118980716A>T
  • NG_124175.1:g.676A>T
  • NG_124176.1:g.157A>T
  • NM_181721.3:c.838A>TMANE SELECT
  • NP_859072.1:p.Met280Leu
  • NC_000011.9:g.118851426A>T
Protein change:
MET280LEU
Links:
OMIM: 615755.0001
Molecular consequence:
  • NM_181721.3:c.838A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004023307OMIM
no assertion criteria provided
Uncertain significance
(Aug 3, 2023)
germlineliterature only

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

Summary from all submissions

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

Citations

PubMed

FOXR1 regulates stress response pathways and is necessary for proper brain development.

Mota A, Waxman HK, Hong R, Lagani GD, Niu SY, Bertherat FL, Wolfe L, Malicdan CM, Markello TC, Adams DR, Gahl WA, Cheng CS, Beffert U, Ho A.

PLoS Genet. 2021 Nov;17(11):e1009854. doi: 10.1371/journal.pgen.1009854.

PubMed [citation]
PMID:
34723967
PMCID:
PMC8559929

Details of each submission

From OMIM, SCV004023307.1

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

Description

This variant is classified as a variant of unknown significance because its contribution to a neurodevelopmental disorder has not been confirmed.

In a patient with severe neurologic symptoms, including microcephaly, progressive brain atrophy, and severe muscle hypotonia, Mota et al. (2021) identified a de novo heterozygous mutation in the FOXR1 gene resulting in a met280-to-leu (M280L) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the parents or in 3 unaffected sibs. FOXR1 with the M280L mutation was expressed in HEK293 cells and resulted in decreased protein expression, which was shown to be due to instability of the mutant protein. The HEK293 cells with the mutant FOXR1 also formed insoluble nuclear aggregates. A comparison of HEK293 cells expressing wildtype and mutant FOXR1 demonstrated that the mutant FOXR1 resulted in decreased expression of genes associated with the heat shock response. The patient had severe muscle hypotonia from early infancy and acquired microcephaly and progressive brain atrophy. He also had growth delay, optic atrophy, cortical visual impairment, and retinitis pigmentosa. A brain MRI showed progressive hypoplasia of the cerebral cortex, pons and cerebellum from age 1 to 5 years. The patient also had a mutation in the ATP1A3 gene (182350), which was thought to contribute to the phenotype.

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

Last Updated: Oct 28, 2023