Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001349317 | SCV001543654 | uncertain significance | Rhabdoid tumor predisposition syndrome 2 | 2020-04-09 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the SMARCA4 gene (p.Gln1415*). However, it is currently unclear if variants that occur in this region of the gene cause disease. Tissue-specific transcript isoforms that skip in-frame exon 30 (also referred as exon 28B in the literature) have been described (PMID: 18437052), questioning the clinical significance of deleting this exon through alternative splicing and/or whole exon deletion. Although loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002), the clinical significance of truncating (nonsense, frameshift) variants within exon 30 are uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with SMARCA4-related conditions. This variant is not present in population databases (ExAC no frequency). |
| Ambry Genetics | RCV002329340 | SCV002626944 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-27 | criteria provided, single submitter | clinical testing | The p.Q1415* variant (also known as c.4243C>T), located in coding exon 29 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4243. This changes the amino acid from a glutamine to a stop codon within coding exon 29. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, this region of the SMARCA4 gene is excluded from other biologically relevant transcripts. Loss-of-function variants in SMARCA4 are known to cause rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT); however, such associations with neurodevelopmental disorders are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. |