Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001017402 | SCV001178478 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-07-31 | criteria provided, single submitter | clinical testing | PLEASE SELECT CORRECT RD FOR YOUR CASE - EDIT IN THE REPORT VUS (CANCER) The p.R377H variant (also known as c.1130G>A), located in coding exon 9 of the SMARCB1 gene, results from a G to A substitution at nucleotide position 1130. The arginine at codon 377 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in patients with Coffin-Siris syndrome and DOORS syndrome (Tsurusaki Y et al. Nat. Genet. 2012 Mar;44:376-8; Kosho T et al. Am. J. Med. Genet. A. 2013 Jun;161A:1221-37; Campeau PM et al. Am. J. Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:327-32; Kosho T et al. Am. J Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:262-75). It has also been identified as a somatic variant in multiple tumor types including meningiomas (Schmitz U et al. Br. J. Cancer. 2001 Jan;84:199-201; Torres-Martín M et al. Cancer Genet. 2015 Jun;208:327-32; Tang M et al. Oncotarget. 2017 Mar;8:17070-17080), gastric cancers (Kim JG et al. Cancer Lett. 2013 Mar;330:33-40; Takeshima H et al. Cancer Lett., 2015 Feb;357:328-338), odontogenic tumors (Brown NA et al. Clin. Cancer Res. 2014 Nov;20:5517-26), sarcomas (Andersson C et al. Cancer Genet, 2016 Apr;209:154-60), and schwannomas (Paganini I et al. J. Neurooncol. 2018 Mar;137:33-38). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear for hereditary cancer predisposition . VLP (NEURO) The p.R377H variant (also known as c.1130G>A), located in coding exon 9 of the SMARCB1 gene, results from a G to A substitution at nucleotide position 1130. The arginine at codon 377 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected de novo in an individual with Coffin-Siris syndrome (Tsurusaki Y et al. Nat. Genet. 2012 Mar;44:376-8; Kosho T et al. Am. J. Med. Genet. A. 2013 Jun;161A:1221-37; Kosho T et al. Am. J Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:262-75). This variant was also detected de novo in two individuals with DOORS syndrome (Campeau PM et al. Am. J. Med. Genet. C Semin. Med. Genet. 2014 Sep;166C:327-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV001238882 | SCV001411715 | pathogenic | not provided | 2020-10-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 22426308, 25169651). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30203). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 377 of the SMARCB1 protein (p.Arg377His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. |
| OMIM | RCV000023124 | SCV000044415 | pathogenic | Intellectual disability, autosomal dominant 15 | 2012-03-18 | no assertion criteria provided | literature only |