Submissions for variant NM_003072.5(SMARCA4):c.335C>T (p.Pro112Leu)

gnomAD frequency: 0.00001  dbSNP: rs1057523400

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422457	SCV000531806	uncertain significance	not provided	2016-09-20	criteria provided, single submitter	clinical testing	The P112L variant in the SMARCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P112L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P112L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P112L as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459924	SCV000548497	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2023-08-28	criteria provided, single submitter	clinical testing	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 389324). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 112 of the SMARCA4 protein (p.Pro112Leu).
Genome-Nilou Lab	RCV001808821	SCV002056297	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323643	SCV002606773	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-20	criteria provided, single submitter	clinical testing	The p.P112L variant (also known as c.335C>T), located in coding exon 2 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 335. The proline at codon 112 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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). 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.