ClinGen Dosage Sensitivity Curation Page

SYP

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
19377476 Tarpey et al. (2009): Three SYP truncating variants were found in 1,122 XLMR-affected subjects examined (274_275insA, T92fs*45; 177_178CA>GT, N59_K604K*; and 829_832delGACT, D227fs*59). The first two truncating variants segregate with the disease (combined lod score 1.7). Samples were not available for segregation evaluation on the third mutation. There were no truncating variants in 1,401 controls. A missense variant (649G>C, G217R) found in a single subject with intellectual disability at an amino acid residue that is highly conserved and which segregated with intellectual disability (lod score 1.8) was also thought to be implicated in disease causation.

Haploinsufficiency phenotype comments:

From Tarpey et al. 2009: In the three families with truncating variants, intellectual disability was mild to moderate and there were no consistent additional features, although epilepsy was noted in some individuals. Female carriers had no manifestations. Since only three families from a single report with no consistent clinical features has been reported in the literature an ISCA rating of 1 has been given.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.