SMARCB1 c.1130G>A, p.(Arg377His)

29 criteria with recorded statuses: 7 met · 10 not met · 2 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

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Identifiers

Gene

SMARCB1

Transcript

NM_003073.4

Coding (HGVS c.)

NM_003073.4:c.1130G>A

Protein (HGVS p.)

NP_003064.2:p.(Arg377His)

GRCh38

chr22:23834152 G>A

GRCh37

chr22:24176339 G>A

ClinVar

30203

Gene diagram

Every interpreted variant in SMARCB1, mapped onto the exon structure of NM_003073.4. Select a row to find it on the plot.

By genetic ancestry

Statements

SpliceAI and Pangolin

Other predictors

REVEL

0.868

BayesDel

0.543

How the predictions were used

Statement

8 paper records listed. 7 cited in the classification.

Cited in the classification

• INI1 mutations in meningiomas at a potential hotspot in exon 9.

  Schmitz U et al. · 2001 Jan

  Identified the somatic c.1130G>A (p.Arg377His) mutation in 4 of 126 meningiomas. The alteration was not observed in 104 healthy individuals or 200 other brain tumors, confirming somatic origin. The Arg377His change falls within the highly conserved C-terminal coiled coil domain and was characterized as a mutational hotspot in exon 9. No functional data on the effect of the mutation were available at the time of publication.

  → PS4 → PM1 Names this variant
  PMID 11161377 ↗
  Source detail

  The alteration was characterized by an G to A transition in the nucleotide 1130 of the coding sequence resulting in an missense mutation of Arg to His in codon 377.

  Location Results and Discussion; Figure 1 (lower panel)

  Context SSCP analysis and Sanger sequencing of meningioma tumor DNA vs matched blood DNA

• Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.

  Tsurusaki Y et al. · 2012 Mar 18

  Identified c.1130G>A (p.Arg377His) as a de novo heterozygous germline mutation in subject 11 with typical Coffin-Siris syndrome, confirmed by Sanger sequencing and absent from 500 Japanese control chromosomes. This was the first report of SMARCB1 mutations causing CSS, establishing the gene-disease association. The mutation was non-truncating, suggesting gain-of-function or dominant-negative effects rather than haploinsufficiency.

  → PS2 → PS4 Names this variant
  PMID 22426308 ↗
  Source detail

  two de novo heterozygous mutations of SMARCB1 were found in 2 affected individuals (c.1130G>A (p.Arg377His) and c.1091_1093del AGA (p.Lys364del))

  Location Results paragraph 1; Table 1 (Subject 11)

  Context Whole-exome sequencing followed by Sanger confirmation; parental testing confirmed de novo

• Comprehensive DNA methylation and extensive mutation analyses reveal an association between the CpG island methylator phenotype and oncogenic mutations in gastric cancers.

  Kim JG et al. · 2013 Mar 1

  Identified the somatic c.1130G>A (p.Arg377His) mutation in SMARCB1 in a gastric cancer sample (S5TP) alongside a KRAS G13D mutation. This was the first report of SMARCB1 mutations in gastric cancer. The mutation was confirmed somatic by dideoxy sequencing of matched non-cancerous tissue.

  → PS4 Names this variant
  PMID 23196062 ↗
  Source detail

  SMARCB1 50 56 c.1130G>A p.Arg377His

  Location Table 1 (Sample S5TP); Results section 3.2; Discussion section

  Context Ion AmpliSeq Cancer Hotspot Panel (55 genes) on 30 gastric cancers; confirmed with dideoxy sequencing

• Activating FGFR2-RAS-BRAF mutations in ameloblastoma.

  Brown NA et al. · 2014 Nov 1

  Identified SMARCB1 R377H as a somatic mutation in 3 of 50 ameloblastomas using the Ion AmpliSeq Cancer Hotspot Panel, all confirmed by Sanger sequencing of matched normal tissue. SMARCB1 (INI-1) immunohistochemistry showed retained protein expression, indicating no loss of protein stability. SMARCB1 mutations co-occurred with activating FGFR2-RAS-BRAF mutations and were suggested to function as secondary mutations in ameloblastoma pathogenesis.

  → PS4 Names this variant
  PMID 24993163 ↗
  Source detail

  SMARCB1 R377H (3). All of these missense mutations were previously described in other neoplasms.

  Location Results section 'Other mutations'; Supplementary Figure S1 and Table S1; Supplementary Figure S2B

  Context Ion AmpliSeq Cancer Hotspot Panel v2 on 50 ameloblastomas with Sanger confirmation and IHC for INI-1

• Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.

  Kosho T et al. · 2014 Sep

  Reviewed genotype-phenotype correlation of CSS caused by SMARCB1 mutations. Patient Y11, a 7-year-old female with the c.1130G>A (p.Arg377His) mutation, exhibited severe neurodevelopmental deficits including severe intellectual disability, seizures, CNS structural abnormalities, scoliosis, sparse scalp hair, thick eyebrows, wide nasal bridge, cleft palate, and hypoplastic 5th fingernails/toenails. The mutation clustered within exons 8-9 at the C-terminus around the SNF5 domain.

  → PS4 Names this variant
  PMID 25168959 ↗
  Source detail

  the p.Arg377His was found in Y11 and also found as a somatic mutation in four meningiomas [Schmitz et al., 2001]

  Location Table I (Patient Y11); Discussion section

  Context Clinical review with genotype-phenotype correlation across 13 SMARCB1-mutated CSS patients

• DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome.

  Campeau PM et al. · 2014 Sep

  Identified the same de novo SMARCB1 c.1130G>A (p.Arg377His) mutation in two patients clinically diagnosed with DOORS syndrome. Both patients had Dandy-Walker malformation, retinal anomalies, respiratory difficulties, scoliosis, rocker bottom feet, and absence of seizures — distinguishing features from TBC1D24-associated DOORS syndrome. One patient died in the first year of life. Authors noted phenotypic overlap with Coffin-Siris syndrome but left the precise clinical classification undecided.

  → PS2 → PS4 Names this variant
  PMID 25169651 ↗
  Source detail

  we identified two patients with a de novo SMARCB1 c.1130G>A, p.Arg377His mutation, confirmed by Sanger sequencing

  Location Abstract; Results (Genotypes section); Table I

  Context Whole exome sequencing with Sanger confirmation; parental testing confirmed de novo

• Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling.

  Directly tested the R377H variant alongside other CSS-associated SMARCB1 CTD mutations. R377H completely disrupted SMARCB1 CTD binding to mononucleosomes in gel-shift assays. Both K364del and R377H mutations led to a reduction in nucleosome crosslinking. mSWI/SNF complexes containing SMARCB1 CTD variants exhibited significant attenuation in nucleosome remodeling activity and reduced ATPase activity on nucleosome substrates. ATAC-seq in SMARCB1-deficient MRT cells showed decreased genome-wide chromatin accessibility with mutant rescue compared to wild-type.

  → PS3 → PM1 Names this variant
  PMID 31759698 ↗
  Source detail

  both K364del and R377H mutations led to a reduction in crosslinking across experiments (Figure 3B-D)

  Location Results; Figures 1F-G, 1H-J, 2B, 3B-D; Figure 4F-G

  Context NMR spectroscopy, photocrosslinking with diazirine probes, nucleosome remodeling restriction enzyme accessibility assays (REAA), ATPase activity assays in HEK-293T SMARCB1-KO cells, ATAC-seq in TTC1240 and G401 MRT cell lines

Other recorded publications

• American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.

  No paper-specific finding is recorded.
  PMID 23619274 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 1,593,918 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 2 Pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

• ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/30203/
• gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-24176339-G-A?dataset=gnomad_r2_1
• gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-23834152-G-A?dataset=gn…
• gnomAD-Canada ↗http://192.168.4.76:8001/variant/22-23834152-G-A
• SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003073.4%3Ac.1130…
• OncoKB ↗www.oncokb.org/gene/SMARCB1/R377H
• COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SMARCB1+c.1130G%3EA
• Cancer hotspots ↗www.cancerhotspots.org/

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.