ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
20137775 Schneppenheim et al. (2010): The authors describe a heterozygous nonsense mutation c.3565C>T (p.Arg1189X) in SMARCA4 in germline DNA derived from an 18-month-old female with a diagnosis of rhabdoid tumor (RT) of the kidney. This mutation was detected in the homozygous state in her tumor tissue. It was also detected in the homozygous state in the rhabdoid tumor tissue of her deceased full sister, and in the heterozygous state in the germline of her apparently unaffected father but not in her mother. The authors state the following as evidence that the SMARCA4 mutation was related to the phenotype: "(1) The RT of both siblings lacked expression of the SMARCA4 protein; (2) Both affected sisters carried the same SMARCA4 nonsense mutation; (3) RT-PCR on the patient's lymphoblastoid cells and expression studies indicated nonsense-mediated decay as the molecular mechanism for the lack of SMARCA4 expression in the tumors; (4) Copy-neutral LOH encompassing the SMARCA4 locus in 19p13 was identified as a ?second hit? in the tumor cells on the background of a balanced genome; (5) The classical RT suppressor gene SMARCB1 and three additional genes coding for core members of the SWI/SNF chromatin-remodeling complex did not show chromosomal or molecular alterations." The authors note that "incomplete penetrance is not truly surprising in RTPS, because it has also been observed in three of nine published families with RTPS due to SMARCB1 mutations. Similarly, incomplete penetrance also exists in SMARCB1?/+ heterozygous mice, in which only 6%?15% of animals develop RTs."
23775540 Witkowski et al. (2013): Describes the case of a woman originally diagnosed with an ovarian immature teratoma following a C-section in 1993. The woman's infant was simultaneously diagnosed with a clonally distinct intracerebral immature teratoma. The authors performed whole exome sequencing on the constitutional DNA from both individuals and discovered a c.3533G>A; p.Trp1178Ter mutation in SMARCA4 in both mother and child; the authors demonstrated that this mutation was subject to nonsense-mediated decay. Tumor analysis by Sanger sequencing revealed a somatic SMARCA4 mutation, both in the mother (c.2438+1G>T), and in her daughter (c.3229C>T; p.Arg1077*), which are predicted to be truncating, in addition to the shared germline mutation. The authors report that "histopathological and immunohistochemical re-analysis of the daughter's tumour revealed that it was indeed a rhabdoid tumour (atypical teratoid/rhabdoid tumour). In this context, the original pathology report of the mother's ovarian tumour was re-interpreted as describing a malignant rhabdoid tumour of the ovary."

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.