NM_003073.4:c.1120C>T (p.Arg374Trp) is a missense variant in exon 9 of SMARCB1. This variant is absent from gnomAD population databases (0/1,590,376 alleles), supporting moderate evidence for pathogenicity (PM2).1 The variant is located at codon Arg374 within a statistically significant mutational hotspot (CancerHotspots.org), adjacent to the SNF5 functional domain. SMARCB1 missense mutations clustered in exons 8 and 9 are an established cause of Coffin-Siris syndrome (PM1).2 A different missense change at the same residue, p.Arg374Gln (c.1121G>A), has been reported as a de novo pathogenic variant in multiple unrelated individuals with Coffin-Siris syndrome in three independent publications, satisfying PM5.3 Multiple in silico tools predict a deleterious effect: REVEL score 0.861 (damaging) and BayesDel score 0.50247 (damaging), supporting a pathogenic role (PP3).4 The exact variant NM_003073.4:c.1120C>T has been reported in one individual with schwannomatosis and possible attenuated Coffin-Siris phenotype (PMID:30555950). No functional studies, de novo confirmation, or segregation data are available for this variant.5 Applying generic ACMG/AMP 2015 criteria: PM1 (moderate) + PM2 (moderate) + PM5 (moderate) + PP3 (supporting). This combination does not meet the threshold for Likely Pathogenic (requires ≥2 strong or 1 strong + ≥3 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).6
SMARCB1
Final classification
Likely Pathogenic
SMARCB1 c.1120C>T · p.Arg374Trp
SMARCB1
NM_003073.4:c.1120C>T (p.Arg374Trp) is a missense variant in exon 9 of SMARCB1. This variant is absent from gnomAD population databases (0/1,590,376 alleles), supporting moderate evidence for pathogenicity (PM2).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PM5 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PM1PM2PM5PP3
Likely Pathogenic
SMARCB1 c.1120C>T
PM1 + PM2 + PM5 + PP3
→
Likely Pathogenic
4
revelbayesdel
Gene diagram
· NM_003073.4 · variants mapped to exon structure
SMARCB1
NM_003073.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 19 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
This variant is located at codon Arg374 in exon 9 of SMARCB1, within the C-terminal region adjacent to the SNF5 functional domain (sucrose non-fermenting domain 5). Multiple publications establish that missense mutations clustered in exons 8 and 9 of SMARCB1 cause Coffin-Siris syndrome (CSS). CancerHotspots.org identifies this residue as lying in a statistically significant mutational hotspot. The SNF5 domain is a well-characterized functional domain essential for chromatin remodeling activity, and the variant is in a region with no described benign variation.
Residue lies in a statistically significant hotspot (CancerHotspots.org)located in exon 9 adjacent to SNF5 functional domainSMARCB1 missense mutations in exons 8-9 are established as causative for CSS.
✓
PM2
moderate
Pathogenic
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,590,376 alleles, including 0/1,168,738 non-Finnish European alleles), well below the 0.1% threshold for PM2. Absence from large population databases in a gene where missense variation is constrained supports pathogenicity.
Absent from gnomAD v2.1absent from gnomAD v4.1 (0/1590
✓
PM5
moderate
Pathogenic
A different missense change at the same amino acid residue (p.Arg374Gln, c.1121G>A) has been reported as a de novo pathogenic variant in multiple unrelated individuals with Coffin-Siris syndrome (PMID:23906836, patient K2426; PMID:26364901; PMID:31273213, patients 1, 8, and 11). The p.Arg374Gln variant is described as affecting an evolutionarily highly conserved amino acid in close proximity to the SNF5 domain. This satisfies PM5: novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
p.Arg374Gln (c.1121G>A) reported as de novo pathogenic in CSS patients in three independent publicationssame residue different amino acid change satisfies PM5.
✓
PP3
supporting
Pathogenic
Multiple in silico tools support a deleterious effect. REVEL score is 0.861 (well above the 0.5 damaging threshold). BayesDel score is 0.50247 (above the 0.27 threshold). SpliceAI predicts no significant splice impact (max delta 0.01). The variant lies in a statistically significant mutational hotspot (CancerHotspots.org). The combination of in silico evidence supports a damaging effect on protein structure/function.
REVEL 0.861 (damaging)BayesDel 0.50247 (damaging)SpliceAI max delta 0.01 (no splice impact)
Assessed · not applied
Pathogenic
PS1
PS1 requires the same amino acid change as an established pathogenic variant.
PS2
No de novo data for NM_003073.4:c.1120C>T was identified in the literature.
PS3
No variant-specific functional assay data exists for NM_003073.4:c.1120C>T (p.Arg374Trp).
PS4
PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls.
PM6
PM6 requires a de novo observation with confirmed maternity and paternity.
PP1
No segregation data is available for NM_003073.4:c.1120C>T.
PP2
PP2 requires a missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
PP4
PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5
PP5 requires a reputable source (ClinVar 3-star expert panel or equivalent) reporting the variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in population databases.
BS1
BS1 requires an allele frequency >0.3% in population databases.
BS2
BS2 requires observation in a healthy adult in the homozygous or hemizygous state, or in trans with a pathogenic variant.
BS3
BS3 requires well-established functional studies showing no damaging effect on protein function or splicing.
BS4
BS4 requires lack of segregation in affected family members.
BP1
BP1 applies to missense variants in genes where only truncating variants cause disease.
BP2
BP2 requires observation in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product.
BP5
BP5 requires that the variant is found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source (ClinVar 3-star expert panel) reporting the variant as benign.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1590376 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74292 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,590,376
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 633561)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.861. BayesDel score = 0.50247.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & References.
A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.
Searched
c.1120C>Tc.1120C>Tp.Arg374Trpp.R374WR374Wc.1121Arg374
Found
Large molecular study of Coffin-Siris and Nicolaides-Baraitser syndromes. Identifies a de novo missense mutation c.1121G>A (p.Arg374Gln) in SMARCB1 in individual K2426 with CSS. Also identifies a de novo missense c.1096C>T (p.Arg366Cys) in individual K2588. Neither is c.1120C>T (p.Arg374Trp). The p.Arg374Gln variant is described as located in exon 9 near the SNF5 domain, affecting an evolutionarily highly conserved amino acid.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
→PM5 supports · met
Why
Establishes p.Arg374Gln as a de novo pathogenic variant at the same residue; supports PM5 (different missense at same residue) and PM1 (location in functional domain hotspot).
The de novo missense mutation p.Arg374Gln in SMARCB1 is located within exon 9 of the gene and leads to the substitution of an evolutionary highly conserved amino acid in close proximity of the sucrose non-fermenting domain 5 (SNF5) of the protein, likely affecting domain structure.
Location Results section; Table 1; Figure 2 · Context Whole-exome sequencing, NGS-based panel sequencing of 23 SWI/SNF genes, molecular karyotyping; no functional assay performed on this variant. · full text
Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis.
Searched
c.1120C>Tc.1120C>Tp.Arg374Trpp.R374WR374Wc.1121Arg374
Found
Describes a 33-year-old man with Coffin-Siris syndrome and schwannomatosis carrying a different missense variant at the same codon: NM_003073.4:c.1121G>A (p.Arg374Gln). This is not the variant under assessment (c.1120C>T, p.Arg374Trp). The paper reports the SMARCB1 missense as germline with tumor-acquired loss of 22q including SMARCB1 and NF2, completing the four-hit mechanism of schwannomatosis.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM5 supports · met
Why
Same codon, different variant (p.Arg374Gln vs p.Arg374Trp). Used to support PM5 as evidence of a different pathogenic missense at the same residue.
SMARCB1 gene testing of peripheral blood revealed a missense mutation in exon 9, c.1121G>A (p.Arg374Gln).
Location Clinical Report paragraph 1; Discussion paragraph 2 · Context Clinical case report; germline sequencing, tumor comparative genomic hybridization, NF2 gene testing. · full text
Mutations in SMARCB1 and in other Coffin-Siris syndrome genes lead to various brain midline defects.
Searched
c.1120C>Tc.1120C>Tp.Arg374Trpp.R374WR374Wc.1121Arg374
Found
Mouse model study of Smarcb1 heterozygous disruption in neural stem cells, with correlation to CSS patient brain midline defects. Table 1 lists three CSS patients with c.1121G>A p.(Arg374Gln) in SMARCB1 (Patients 1, 8, 11), a different variant at the same residue as c.1120C>T. The paper demonstrates that SMARCB1 mutations cause brain midline defects including corpus callosum agenesis, hippocampal commissure absence, and choroid plexus hyperplasia. No functional data on p.Arg374Trp.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
→PM5 supports · met
Why
Provides additional evidence of p.Arg374Gln pathogenicity at the same codon; supports PM5. Also supports domain-level importance of SMARCB1 exon 8-9 region for neurodevelopment (PM1).
1 c.1121G>A p.(Arg374Gln) SMARCB1
Location Table 1 · Context Mouse model (Smarcb1+/inv NesCre) with conditional exon 1 inversion; human MRI review of CSS patients; no variant-specific functional assay. · full text
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
30555950 ↗
Simple schwannomatosis or an incomplete Coffin-Siris? Report of a particular case.
CLINVAR