Submissions for variant NM_003072.5(SMARCA4):c.973G>A (p.Val325Met)

gnomAD frequency: 0.00001  dbSNP: rs1361910224

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561138	SCV000664150	likely benign	Hereditary cancer-predisposing syndrome	2022-09-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702172	SCV000831013	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2025-01-28	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 325 of the SMARCA4 protein (p.Val325Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 480591). 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.
Genome-Nilou Lab	RCV001809574	SCV002056393	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561138	SCV002535261	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-01	criteria provided, single submitter	curation
Baylor Genetics	RCV000702172	SCV004204894	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2024-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525976	SCV005040024	uncertain significance	not specified	2024-03-29	criteria provided, single submitter	clinical testing	Variant summary: SMARCA4 c.973G>A (p.Val325Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 1598980 control chromosomes. This frequency does not allow for any conclusion about variant significance. However, autosomal dominant Coffin-Siris Syndrome is expected to result in some generally early-onset phenotypes (with variable severity), and this variant is present in 13 heterozygous individuals in gnomAD, suggesting that it may have a benign role in this condition. To our knowledge, no occurrence of c.973G>A in individuals affected with Coffin-Siris Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 480591). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.