ClinVar Miner

Submissions for variant NM_003073.5(SMARCB1):c.1121G>A (p.Arg374Gln) (rs1057517825)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412754 SCV000490818 pathogenic not provided 2016-03-17 criteria provided, single submitter clinical testing The R374Q pathogenic variant in the SMARCB1 gene has been reported previously in a child with Coffin-Siris syndrome (CSS) who harbored a de novo R374Q variant (Wieczorek et al., 2013), as well as an adult male with CSS and schwannomatosis (Gossai et al., 2015). The R374Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R374Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R374Q as a pathogenic variant.
Ambry Genetics RCV000622632 SCV000741911 pathogenic Inborn genetic diseases 2016-11-22 criteria provided, single submitter clinical testing
Invitae RCV000412754 SCV000940629 likely pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 374 of the SMARCB1 protein (p.Arg374Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Coffin-Siris syndrome (PMID: 23906836, 26364901, Invitae). ClinVar contains an entry for this variant (Variation ID: 372511). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Baylor Genetics RCV000850606 SCV000992837 likely pathogenic Mental retardation, autosomal dominant 15 2017-12-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV001533136 SCV001748956 pathogenic SMARCB1-related BAFopathy 2021-06-10 criteria provided, single submitter clinical testing

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