Submissions for variant NM_003072.5(SMARCA4):c.305G>T (p.Gly102Val)

gnomAD frequency: 0.00001  dbSNP: rs746602808

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562895	SCV000664030	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-19	criteria provided, single submitter	clinical testing	The p.G102V variant (also known as c.305G>T), located in coding exon 2 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 305. The glycine at codon 102 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806778	SCV000946795	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2024-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 102 of the SMARCA4 protein (p.Gly102Val). This variant is present in population databases (rs746602808, gnomAD 0.006%). 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: 480560). 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) 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.
Mendelics	RCV000806778	SCV001140975	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001809560	SCV002056289	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821664	SCV002070104	uncertain significance	not specified	2021-10-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SMARCA4 gene demonstrated a sequence change, c.305G>T, in exon 3 that results in an amino acid change, p.Gly102Val. This sequence change has been described in the gnomAD database with a frequency of 0.0054% in the East Asian subpopulation (dbSNP rs746602808). The p.Gly102Val change affects a poorly conserved amino acid residue located in a domain of the SMARCA4 protein that is not known to be functional. The p.Gly102Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with SMARCA4-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly102Val change remains unknown at this time.