Submissions for variant NM_003072.5(SMARCA4):c.4826T>C (p.Leu1609Pro)

gnomAD frequency: 0.00003  dbSNP: rs755493468

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528180	SCV000648134	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2025-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1641 of the SMARCA4 protein (p.Leu1641Pro). This variant is present in population databases (rs755493468, gnomAD 0.008%). This missense change has been observed in individual(s) with neurodevelopmental disorder (PMID: 37500730). ClinVar contains an entry for this variant (Variation ID: 470424). 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	RCV000574151	SCV000663986	likely benign	Hereditary cancer-predisposing syndrome	2020-12-22	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.
Fulgent Genetics, Fulgent Genetics	RCV000765427	SCV000896711	uncertain significance	Rhabdoid tumor predisposition syndrome 2; Intellectual disability, autosomal dominant 16	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001293039	SCV001481265	uncertain significance	Intellectual disability, autosomal dominant 16	2018-12-18	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001293039	SCV002056995	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574151	SCV002535193	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
GeneDx	RCV003153717	SCV003842764	uncertain significance	not provided	2022-09-16	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
PreventionGenetics, part of Exact Sciences	RCV003960355	SCV004782102	likely benign	SMARCA4-related disorder	2023-11-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).