Submissions for variant NM_003072.5(SMARCA4):c.659T>C (p.Leu220Pro)

dbSNP: rs1057422480

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798313	SCV000937921	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2024-07-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 220 of the SMARCA4 protein (p.Leu220Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 644405). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV002360937	SCV002662697	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-20	criteria provided, single submitter	clinical testing	The p.L220P variant (also known as c.659T>C), located in coding exon 3 of the SMARCA4 gene, results from a T to C substitution at nucleotide position 659. The leucine at codon 220 is replaced by proline, an amino acid with similar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) 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). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely.
Baylor Genetics	RCV000798313	SCV004204868	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2023-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV004773155	SCV005386421	uncertain significance	not provided	2024-01-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge