Submissions for variant NM_003072.5(SMARCA4):c.3557C>T (p.Ala1186Val)

dbSNP: rs1600388982

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814525	SCV000954938	likely pathogenic	Rhabdoid tumor predisposition syndrome 2	2021-04-01	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 31530938). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 1186 of the SMARCA4 protein (p.Ala1186Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995876	SCV001150261	likely pathogenic	Intellectual disability, autosomal dominant 16	2019-05-07	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000995876	SCV001480420	uncertain significance	Intellectual disability, autosomal dominant 16	2020-07-25	criteria provided, single submitter	clinical testing	The c.3557C>T (p.Ala1186Val) variant in exon 26 of 36 of SMARCA4 in the conserved helicase c domain has been reported once in an individual (de novo) with a diagnosis of Coffin Siris syndrome [PMID: 31530938]. This variant is not present in gnomAD, suggesting it is not a common benign variant in the populations represented in this database. In silico predictors suggest this variant is Damaging (Provean score:-3.4; SIFT score:0.001). Given the current evidences regarding its pathogenicity, the c.3557C>T (p.Ala1186Val) variant identified in the SMARCA4 gene is reported as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000995876	SCV002056205	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002245685	SCV002512842	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24658002, 31530938)
Illumina Laboratory Services, Illumina	RCV000995876	SCV004801626	likely pathogenic	Intellectual disability, autosomal dominant 16	2018-12-13	criteria provided, single submitter	clinical testing	The SMARCA4 c.3557C>T p.(Ala1186Val) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. This variant is located in the SNF2 ATPase domain. The variant was identified in a de novo state in the proband. Based on the available evidence, the c.3557C>T p.(Ala1186Val) variant is classified as likely pathogenic for Coffin-Siris syndrome.