NM_001122757.2(POU1F1):c.889C>T (p.Arg297Trp)

NM_001122757.2(POU1F1):c.889C>T (p.Arg297Trp)

Variant type:
single nucleotide variant
Cytogenetic location:
3p11
Genomic location:
  • Chr3:87309109 (on Assembly GRCh37)
  • Chr3:87259959 (on Assembly GRCh38)
Protein change:
R271W, R297W
HGVS:
  • NG_008225.2:g.21629C>T
  • NM_000306.3:c.811C>T
  • NM_001122757.2:c.889C>T
  • NC_000003.12:g.87259959G>A (GRCh38)
  • NP_000297.1:p.Arg271Trp
  • NP_001116229.1:p.Arg297Trp
  • NC_000003.11:g.87309109G>A (GRCh37)
  • NM_000306.2:c.811C>T
  • NM_001122757.1:c.889C>T
  • NG_008225.1:g.21629C>T
Links:
NCBI 1000 Genomes Browser:
rs104893755
Molecular consequence:
NM_001122757.1:c.889C>T: missense variant [Sequence Ontology SO:0001583]

Clinical significance

NM_001122757.2(POU1F1):c.889C>T (p.Arg297Trp)

Clinical significance:
Pathogenic
Review status:
1 star out of maximum of 4 stars
classified by single submitter
Number of submission(s):
1
Condition(s)
  • Pituitary hormone deficiency, combined 1[MedGen - OMIM]
See supporting ClinVar records

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Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter - Study name
(Last submitted)
Submission accession
Pathogenic
(May 16, 2014)
classified by single submitter
(literature only)
literature only
  • Pituitary hormone deficiency, combined 1[MedGen | OMIM]
germlinePubMed (8)
[See all records that cite these PMIDs]
OMIM

(Dec 30, 2010)

SCV000034827

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermlinenot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

Aarskog et al. (1997) reported a Norwegian patient with the R271W mutation and found reports of 9 other cases in different populations, suggesting that codon 271 in exon 6 is a 'hotspot' for PIT1 mutations. Their patient was a 3-month-old girl with severe growth deficiency from birth as well as distinctive facial features with prominent forehead, marked midfacial hypoplasia with depressed nasal bridge, deep-set eyes, and a short nose with anteverted nostrils. MRI examination showed a hypoplastic pituitary gland. Aarskog et al. (1997) designed a specific amplification-created restriction site assay for the R271W mutation.
In 5 patients with CPHD, including a mother and daughter and an unrelated mother and son with CPHD, Turton et al. (2005) identified heterozygosity for the R271W mutation in the POU1F1 gene. Noting that Okamoto et al. (1994) had suggested that the R271W mutation might be variably penetrant, possibly because of monoallelic expression, Turton et al. (2005) stated that their data and those of de Zegher et al. (1995) did not support that hypothesis.
In a mother and daughter with combined pituitary hormone deficiency, de Zegher et al. (1995) identified heterozygosity for the R271W mutation in the PIT1 gene. At birth, serum T4 was undetectable in mother and infant, and the newborn presented with a striking delay of respiratory, cardiovascular, neurological, and bone maturation. de Zegher et al. (1995) concluded that thyroid hormone is a potent endogenous driver of fetal maturation and that under ordinary circumstances, placental transfer of maternal T4 is a rescue mechanism for infants with congenital hypothyroidism, preventing fetal and neonatal symptoms of thyroid deficiency and safeguarding developmental potential.
Martineli et al. (1998) described the case of a 38-year-old woman, born to consanguineous parents, presenting with growth failure and hypothyroidism. Growth failure was noted in early infancy, whereas hypothyroidism had been apparent only from adolescence. She had almost undetectable growth hormone and prolactin levels and an inappropriately low TSH, while the remaining pituitary evaluation was normal. The pituitary gland was hypoplastic by magnetic resonance imaging. The point mutation in exon 6, present in homozygous form, was a C-to-T substitution that changed amino acid 271 from arg to trp.
Okamoto et al. (1994) likewise reported a Japanese patient heterozygous for the arg271-to-trp mutation who showed typical clinical features, presumably as the result of a dominant-negative effect. However, her father, grandmother, and 2 aunts had the same mutation without clinical symptoms. By RT-PCR, Okamoto et al. (1994) analyzed the PIT1 transcript in peripheral lymphocytes and found monoallelic expression of the normal allele in the father and grandmother and skewed pattern of biallelic expression in the proband. Thus, there appears to be an epigenetic control on the expression of the PIT1 gene. One explanation for the monoallelic expression is genomic imprinting. Possibly the mutant PIT1 gene silent in the grandmother and the father was reactivated through spermatogenesis in the father, and thus manifested in the granddaughter with a dominant-negative effect.
Radovick et al. (1992) identified a C-to-T transition in codon 271 in approximately one-half of clones of the PIT1 gene from a patient with deficiency of growth hormone, prolactin, and TSH (CPHD1; 613038), which was manifest as severe mental retardation and short stature (Rogol and Kahn, 1976). The patient appeared to have a de novo mutation. Radovick et al. (1992) demonstrated that the mutant gene product bound DNA normally but acted as a dominant inhibitor of the action of the gene in the pituitary. This is, then, an example of dominant-negative mutation. In a Japanese child with combined pituitary hormone deficiency, Ohta et al. (1992) found the same mutation in heterozygous state.

Last Updated: Apr 3, 2015