Submissions for variant NM_003072.5(SMARCA4):c.2021C>T (p.Pro674Leu)

gnomAD frequency: 0.00001  dbSNP: rs747463080

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473248	SCV000548390	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 674 of the SMARCA4 protein (p.Pro674Leu). This variant is present in population databases (rs747463080, 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: 408611). 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 80%. 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	RCV000572766	SCV000664109	likely benign	Hereditary cancer-predisposing syndrome	2022-07-29	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003233641	SCV002010720	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001809352	SCV002056480	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000572766	SCV002532807	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
GeneDx	RCV003233641	SCV003930447	uncertain significance	not provided	2022-12-07	criteria provided, single submitter	clinical testing	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
Baylor Genetics	RCV000473248	SCV004204945	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2023-08-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745396	SCV005354107	uncertain significance	SMARCA4-related disorder	2024-03-29	no assertion criteria provided	clinical testing	The SMARCA4 c.2021C>T variant is predicted to result in the amino acid substitution p.Pro674Leu. This variant was reported in a large neurodevelopmental disorder cohort; however, detailed clinical information was not available (Table S1, Valencia et al. 2023. PubMed ID: 37500730). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408611/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.