Submissions for variant NM_003072.5(SMARCA4):c.4405G>A (p.Val1469Met)

gnomAD frequency: 0.00002  dbSNP: rs370484739

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000646873	SCV000768658	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1501 of the SMARCA4 protein (p.Val1501Met). This variant is present in population databases (rs370484739, gnomAD 0.007%). 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: 537817). Invitae Evidence 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 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. 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	RCV001022598	SCV001184352	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-17	criteria provided, single submitter	clinical testing	The p.V1501M variant (also known as c.4501G>A), located in coding exon 30 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 4501. The valine at codon 1501 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in an individual with features of Coffin-Siris syndrome and was classified as a variant of unknown significance (Santen GW et al. Hum Mutat, 2013 Nov;34:1519-28). This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). 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 rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely.
Genome-Nilou Lab	RCV001809727	SCV002056942	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000646873	SCV005052748	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2024-02-14	criteria provided, single submitter	clinical testing