Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000687557 | SCV000815132 | likely pathogenic | Rhabdoid tumor predisposition syndrome 2 | 2021-06-28 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals with SMARCA4-related conditions. This variant has been observed in individuals that did not have SMARCA4-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 567464). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg1523*) in the SMARCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). |
| Ambry Genetics | RCV001022708 | SCV001184475 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-09 | criteria provided, single submitter | clinical testing | The p.R1523* pathogenic mutation (also known as c.4567C>T), located in coding exon 31 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4567. This changes the amino acid from an arginine to a stop codon within coding exon 31. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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, this alteration is pathogenic for rhabdoid tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unlikely. |