Variant classification summary

NM_003073.4:c.1130G>A

SMARCB1 · NP_003064.2:p.(Arg377His) · NM_003073.4

GRCh37: chr22:24176339 G>A · GRCh38: chr22:23834152 G>A

Gene: SMARCB1 Transcript: NM_003073.4

Final call

Pathogenic

PS2 strong PS3 moderate PS4 supporting PM1 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

SMARCB1

Transcript

NM_003073.4

Protein

NP_003064.2:p.(Arg377His)

gnomAD AF

1.254769693296644e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Three independent de novo occurrences of c.1130G>A have been confirmed with parental testing in patients with Coffin-Siris syndrome / DOORS spectrum phenotype (Tsurusaki et al. 2012, Campeau et al. 2014).

2

Functional studies (Valencia et al. 2019) demonstrate that the R377H variant completely disrupts SMARCB1 C-terminal domain binding to the nucleosome acidic patch, significantly attenuates mSWI/SNF chromatin remodeling activity, and reduces ATPase activity on nucleosome substrates.

3

Codon 377 lies within the SMARCB1 C-terminal domain, a well-characterized functional domain essential for nucleosome binding and chromatin remodeling, and is a confirmed mutational hotspot in both germline and somatic disease contexts.

4

The variant is absent from gnomAD v2.1 (0/216,632 alleles) and extremely rare in gnomAD v4.1 (2/1,593,918 alleles; AF=1.25e-6), meeting the population frequency criterion for PM2.

5

Multiple in silico tools predict a deleterious effect (REVEL 0.868, BayesDel 0.543), supporting PP3.

6

This variant is classified as Pathogenic in ClinVar by two clinical laboratories, supporting PP5.

7

This variant has been observed in at least 12 affected individuals across multiple publications in both germline (CSS, DOORS) and somatic (meningioma, ameloblastoma, gastric cancer) disease contexts.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_003073.4:c.1130G>A is a missense variant (p.Arg377His) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to non-truncating variants under the ClinGen SVI PVS1 decision tree (PMC6185798).
PS1	N/A	PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change as a previously established pathogenic variant. The variant being assessed is itself the only known nucleotide change producing p.Arg377His; no prior-established pathogenic variant with a different underlying nucleotide change exists at this position.
PS2	Met	Three independent de novo occurrences of c.1130G>A (p.Arg377His) have been confirmed with parental testing across two publications. Tsurusaki et al. (2012, PMID:22426308) identified a de novo c.1130G>A mutation in a CSS patient (subject 11), confirmed by Sanger sequencing and absent from 500 control chromosomes. Campeau et al. (2014, PMID:25169651) identified two additional patients with the same de novo SMARCB1 c.1130G>A mutation, both confirmed by Sanger sequencing. All three patients presented with phenotypes consistent with Coffin-Siris syndrome / DOORS syndrome spectrum. Multiple independent de novo observations with confirmed parentage in affected individuals with consistent phenotype support PS2 at strong level.	PMID:22426308 PMID:25169651
PS3	Met	Valencia et al. (2019, PMID:31759698) directly tested the R377H variant in a comprehensive biochemical and functional characterization of the SMARCB1 C-terminal domain. The R377H mutation completely disrupted nucleosome binding by the SMARCB1 CTD peptide in gel-shift assays. Both K364del and R377H mutations led to a reduction in nucleosome crosslinking across experiments. Complexes containing SMARCB1 CTD mutant variants (including R377H) exhibited significant attenuation in nucleosome remodeling activity and a significant reduction in ATPase activity when bound to nucleosome substrates. ATAC-seq in rescue experiments showed decreased genome-wide chromatin accessibility with mutant SMARCB1 relative to wild-type. This is variant-specific functional evidence from a single systematic study; moderate strength is assigned per PS3 calibration (single study with systematic characterization directly testing the variant).	PMID:31759698
PS5	N/A	PS5 applies when a reputable source reports the variant as pathogenic but the evidence is not available for independent evaluation. In this case, the primary evidence cited by ClinVar submitters (PMIDs: 11161377, 22426308, 25169651, 31759698, etc.) was obtained as full text and independently reviewed. The evidence is available and has been evaluated; PS5 is therefore not applicable.
PS4	Met	This variant has been observed in multiple affected individuals across several publications in both germline and somatic contexts. Tsurusaki et al. (2012, PMID:22426308) reported 1 de novo germline case with CSS; Kosho et al. (2014, PMID:25168959) reviewed an additional germline case (Y11) with CSS; Campeau et al. (2014, PMID:25169651) reported 2 additional de novo germline cases; Schmitz et al. (2001, PMID:11161377) identified 4 somatic cases in meningiomas; Brown et al. (2014, PMID:24993163) identified 3 somatic cases in ameloblastomas; Kim et al. (2013, PMID:23196062) identified 1 somatic case in gastric cancer. The variant is absent from gnomAD v2.1 (0/216,632) and present at only 2/1,593,918 alleles (AF=1.25e-6, grpmax FAF=2.8e-7) in gnomAD v4.1. The aggregate case count supports enrichment in affected individuals relative to the general population, meeting PS4 at supporting level.	PMID:22426308 PMID:25168959 PMID:25169651 PMID:11161377 PMID:24993163 PMID:23196062 gnomad_v2 gnomad_v4
PM1	Met	Codon 377 lies within the SMARCB1 C-terminal domain (CTD, aa 351-385), a well-characterized functional domain that directly binds the nucleosome acidic patch and is essential for mSWI/SNF complex-mediated chromatin remodeling activity (PMID:31759698). Schmitz et al. (2001, PMID:11161377) identified this codon as a recurrent mutational hotspot in meningiomas. The variant falls within the highly conserved coiled coil domain at the C-terminus. Both germline (CSS, DOORS) and somatic (meningioma, ameloblastoma, gastric cancer) mutations cluster at this residue. Cancerhotspots.org identifies this as a statistically significant hotspot residue. PM1 at moderate is supported by a well-characterized functional domain with a confirmed mutational hotspot.	PMID:11161377 PMID:31759698
PM2	Met	This variant is absent from gnomAD v2.1 exomes (0/216,632 alleles) and present at extremely low frequency in gnomAD v4.1 (2/1,593,918 alleles, AF=1.25e-6, grpmax FAF=2.8e-7), well below the 0.1% threshold for PM2. The near-complete absence from large population databases supports PM2. Supporting strength is assigned because 2 alleles were detected in v4.1, indicating the variant is not universally absent, though the grpmax filtering allele frequency of 2.8e-7 confirms extreme rarity.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 candidate harvesting did not identify any comparator variants with confirmed classic same-residue PM5 semantics. The pm5_candidates.json analysis found no candidates meeting the threshold for PM5 application.
PM6	N/A	PM6 applies to assumed de novo variants without confirmation of paternity and maternity. The de novo observations for c.1130G>A were all confirmed with parental testing (see PS2). PM6 is superseded by PS2 and is therefore not applicable.
PP1	Not assessed	No segregation data are available for this variant. Co-segregation with disease in multiple affected family members has not been reported in the literature reviewed.
PP2	Not assessed	PP2 requires a computational gene-level missense constraint metric (Z-score) that is not available in the case data. SMARCB1 missense variants in the C-terminal domain are a known disease mechanism for CSS, but the gene-level missense constraint score was not provided in the evidence brief or prefetch data.
PP3	Met	Multiple in silico prediction tools support a deleterious effect for this missense variant. REVEL score of 0.868 is strongly predictive of pathogenicity. BayesDel score of 0.543 is above the deleterious threshold. SpliceAI predicts no splicing impact (max delta 0.00), so the computational evidence is specific to the amino acid substitution rather than a cryptic splice effect. PP3 at supporting level is appropriate given converging in silico evidence.	revel bayesdel spliceai
PP4	Not met	PP4 requires that the patient's phenotype is highly specific for a disease with a single genetic etiology. Coffin-Siris syndrome is genetically heterogeneous, caused by mutations in at least six different SWI/SNF subunit genes (SMARCB1, SMARCA4, SMARCE1, ARID1A, ARID1B, SMARCA2). The phenotype alone is not specific for SMARCB1-related disease.
PP5	Met	This variant is classified as Pathogenic in ClinVar (Variation ID: 30203) by two clinical testing laboratories (Labcorp Genetics/Invitae and Ambry Genetics), both with criteria provided. Although the review status is 1★ (single submitter level), the classification is consistent across submitters and is supported by published literature. Under generic ACMG rules, a reputable clinical laboratory classification of Pathogenic supports PP5 at supporting level.	clinvar
BA1	Not met	The maximum allele frequency of this variant (gnomAD v4.1: AF=1.25e-6, grpmax FAF=2.8e-7) is far below the BA1 threshold of >1%. This variant is extremely rare in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency of this variant (gnomAD v4.1: AF=1.25e-6) is far below the BS1 threshold of >0.3%. The variant is extremely rare and does not support a benign interpretation on population frequency grounds.	gnomad_v4
BS2	Not met	No evidence was found of this variant being observed in healthy adults. All reported observations are in affected individuals (CSS, DOORS, meningioma, ameloblastoma, gastric cancer). BS2 requires observation in a healthy adult individual for a fully penetrant disorder.
BS3	Not met	Functional studies (PMID:31759698) demonstrate a deleterious effect of the R377H variant on SMARCB1 CTD nucleosome binding, crosslinking, chromatin remodeling activity, and ATPase activity. These findings support pathogenicity (PS3) and directly contradict BS3, which requires well-established functional studies showing no deleterious effect.	PMID:31759698
BS4	Not met	No evidence of lack of segregation with disease was identified. All reported familial cases are de novo, and no non-segregation data are available.
BP1	N/A	BP1 applies when a missense variant is found in a gene where primarily truncating variants cause disease. SMARCB1 has a dual disease mechanism: truncating variants cause rhabdoid tumor predisposition syndrome (RTPS1) via loss-of-function, while missense variants in the C-terminal domain cause Coffin-Siris syndrome via dominant-negative or gain-of-function effects. Both variant types are established disease mechanisms, so BP1 is not applicable.
BP2	Not met	No evidence was found of this variant being observed in trans with a known pathogenic SMARCB1 variant. The literature reviewed does not report any cases with biallelic SMARCB1 variants.
BP4	Not met	Multiple in silico tools (REVEL: 0.868; BayesDel: 0.543) predict a deleterious effect. SpliceAI predicts no splicing impact (max delta 0.00). The computational evidence points toward pathogenicity (supporting PP3), not benign impact (BP4).	revel bayesdel spliceai
BP5	Not met	This variant has been observed in multiple affected individuals with a consistent disease phenotype across independent publications (CSS, DOORS). BP5 requires that the variant be found in a case with an alternate molecular basis for disease, which is not the case here.
BP6	Not met	ClinVar classifies this variant as Pathogenic (Variation ID: 30203) by two clinical laboratories. BP6 requires a reputable source to classify the variant as benign, which is contradicted by the existing ClinVar classification.	clinvar
BP7	N/A	BP7 applies specifically to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_003073.4:c.1130G>A is a missense variant resulting in p.Arg377His, not a synonymous variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function — not applicable to a missense substitution.
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. SMARCB1-related CSS is an autosomal dominant disorder; PM3 is not applicable.
PM4	N/A	PM4 applies to protein-length changes from in-frame deletions/insertions or stop-loss variants. This is a missense substitution, not a protein-length-altering variant.

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