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NM_000791.4(DHFR):c.458A>T (p.Asp153Val) AND Constitutional megaloblastic anemia with severe neurologic disease

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Feb 11, 2011
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:
RCV000022525.25

Allele description [Variation Report for NM_000791.4(DHFR):c.458A>T (p.Asp153Val)]

NM_000791.4(DHFR):c.458A>T (p.Asp153Val)

Gene:
DHFR:dihydrofolate reductase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q14.1
Genomic location:
Preferred name:
NM_000791.4(DHFR):c.458A>T (p.Asp153Val)
Other names:
DHFRc.458A>T; DHFRp.D153V; DHFRp.Asp153Val
HGVS:
  • NC_000005.10:g.80633904T>A
  • NG_023304.1:g.26078A>T
  • NM_000791.4:c.458A>TMANE SELECT
  • NM_001290354.2:c.302A>T
  • NM_001290357.2:c.369+3979A>T
  • NP_000782.1:p.Asp153Val
  • NP_001277283.1:p.Asp101Val
  • NC_000005.9:g.79929723T>A
  • NM_000791.3:c.458A>T
  • NR_110936.2:n.775A>T
  • P00374:p.Asp153Val
Protein change:
D101V; ASP153VAL
Links:
UniProtKB: P00374#VAR_065819; OMIM: 126060.0002; dbSNP: rs121913223
NCBI 1000 Genomes Browser:
rs121913223
Molecular consequence:
  • NM_001290357.2:c.369+3979A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000791.4:c.458A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001290354.2:c.302A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_110936.2:n.775A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Constitutional megaloblastic anemia with severe neurologic disease
Synonyms:
DHFR DEFICIENCY; Megaloblastic anemia due to dihydrofolate reductase deficiency
Identifiers:
MONDO: MONDO:0013456; MedGen: C3151205; Orphanet: 319651; OMIM: 613839

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000043814OMIM
no assertion criteria provided
Pathogenic
(Feb 11, 2011) 		germlineliterature only

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

SCV000148827Clinic of Pediatric and Adolescent Medicine, University Hospital Ulm
no assertion criteria provided
pathogenicgermlinenot provided

PubMed (3)
[See all records that cite these PMIDs]

Description

dihydrofolate reductase (DHFR) deficiency. Causes macrocytic anemia and neurologic disease (atypical childhood absence epilepsy);variable phenotypic expression;treatment with follinic acid leads to normal blood counts and improvement of neurologic symptoms. Manuscript submitted for publication, therefore public release of this dbSNP submission only from the time of publication.

SCV000148827

Causes macrocytic anemia and neurologic disease (atypical childhood absence epilepsy);variable phenotypic expression; treatment with follinic acid leads to normal blood counts and improvement of neurologic symptoms.

SCV000148827

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot provided1not providedliterature only

Citations

PubMed

Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease.

Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K.

Am J Hum Genet. 2011 Feb 11;88(2):226-31. doi: 10.1016/j.ajhg.2011.01.007.

PubMed [citation]
PMID:
21310277
PMCID:
PMC3035706

Dihydrofolate reductase deficiency causing megaloblastic anemia in two families.

Tauro GP, Danks DM, Rowe PB, Van der Weyden MB, Schwarz MA, Collins VL, Neal BW.

N Engl J Med. 1976 Feb 26;294(9):466-70.

PubMed [citation]
PMID:
1060915
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000043814.2

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

Description

In 3 affected sibs, born of distantly related parents of European descent, with megaloblastic anemia due to dihydrofolate reductase deficiency (613839), Cario et al. (2011) identified a homozygous 458A-T transversion in exon 5 of the DHFR gene, resulting in an asp153-to-val (D153V) substitution. Both parents were heterozygous for the D153V mutation, which was not found in 120 control samples. The mutation was predicted to interrupt hydrogen bonding, affecting fold and conformational stability, resulting in decreased enzyme activity. Studies of patient lymphoblastoid cells showed that DHFR activity was reduced to about 10% of control levels. DHFR expression was similar to controls, but protein levels were severely decreased. Although 1 sib was essentially unaffected except for macrocytosis, the other 2 sibs developed childhood absence epilepsy with eyelid myoclonia in childhood. One had learning disabilities. Levels of 5-methyltetrahydrofolate (5-MTHF) in the CSF were low, but improved with folinic acid treatment.

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

From Clinic of Pediatric and Adolescent Medicine, University Hospital Ulm, SCV000148827.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot provided PubMed (3)

Description

Converted during submission to Pathogenic.

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

Last Updated: Apr 23, 2022