ClinVar contains an entry for this variant (Variation ID: 68770). 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. This variant disrupts the p.Arg1105 amino acid residue in SMARCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366787). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA2 protein function. This missense change has been observed in individuals with Nicolaides-Baraitser syndrome (PMID: 22366787; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1105 of the SMARCA2 protein (p.Arg1105Pro).
ClinVar Genomic variation as it relates to human health
NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro)
Variation ID: 68770 Accession: VCV000068770.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p24.3 9: 2110275 (GRCh38) [ NCBI UCSC ] 9: 2110275 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 31, 2013 Feb 14, 2024 Oct 31, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003070.5:c.3314G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003061.3:p.Arg1105Pro missense NM_001289396.2:c.3314G>C NP_001276325.1:p.Arg1105Pro missense NM_001289397.2:c.3140G>C NP_001276326.1:p.Arg1047Pro missense NM_139045.4:c.3314G>C NP_620614.2:p.Arg1105Pro missense NC_000009.12:g.2110275G>C NC_000009.11:g.2110275G>C NG_032162.2:g.134986G>C LRG_882:g.134986G>C LRG_882t1:c.3314G>C LRG_882p1:p.Arg1105Pro P51531:p.Arg1105Pro - Protein change
- R1105P, R1047P
- Other names
- -
- Canonical SPDI
- NC_000009.12:2110274:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SMARCA2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1207 | 1381 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2023 | RCV000059671.11 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Jun 20, 2022 | RCV002255112.10 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004295974.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 68770). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data … (more)
ClinVar contains an entry for this variant (Variation ID: 68770). 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. This variant disrupts the p.Arg1105 amino acid residue in SMARCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366787). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA2 protein function. This missense change has been observed in individuals with Nicolaides-Baraitser syndrome (PMID: 22366787; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1105 of the SMARCA2 protein (p.Arg1105Pro). (less)
|
|
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Likely pathogenic
(Jun 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Nicolaides-Baraitser syndrome
Nicolaides-Baraitser syndrome (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002526442.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Clinical Features:
Downslanted palpebral fissures (present) , Global developmental delay (present) , Abnormal bleeding (present) , Sparse scalp hair (present) , Poor motor coordination (present) , EEG … (more)
Downslanted palpebral fissures (present) , Global developmental delay (present) , Abnormal bleeding (present) , Sparse scalp hair (present) , Poor motor coordination (present) , EEG abnormality (present) , Language disorder (present) , Prolonged bleeding time (present) , Decreased mean platelet volume (present) , Abnormal tragus morphology (present) , Abnormal platelet function (present) , Impaired continence (present) , Reduced blood folate concentration (present) , Decreased circulating vitamin D concentration (present) (less)
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Likely pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004170082.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated … (more)
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22366787, 35811451, 24090879) (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Nicolaides-Baraitser syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Child and Adolescent Psychiatry Residency Program, Foundation for Education and Research in Health Sciences
Accession: SCV003930365.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls PM1: Located in a mutational hot spot … (more)
PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls PM1: Located in a mutational hot spot and/or critical and well-established functional domain PM2: Absent from controls (or at extremely low frequency if recessive) from ExAC, 1000Genomas, A3raM, TOPMED, and population databases. PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (p.R1105H, p.R1105C) (Sousa, Hennekam; Nicolaides-Baraitser Syndrome International Consortium, 2014). PM6: variant described as de novo, without confirmatory maternity and paternity analysis. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product [CADD = 34.0]. (less)
Clinical Features:
short stature (present) , low weight (present) , failure to thrive (present) , microcephaly (present) , triangular face (present) , dowslanting palpebral fissure (present) , … (more)
short stature (present) , low weight (present) , failure to thrive (present) , microcephaly (present) , triangular face (present) , dowslanting palpebral fissure (present) , sagging periorbital skin (present) , large mouth (present) , anteverted nares (present) , thin upper vermillion (present) , delayed teeth eruption (present) , wrinkly skin (present) , eczema (present) , pale skin (present) , sparse hair (present) , dense eyelashes (present) , Cryptorchidism (present) , absense of speech (present) , short phalanges (present) , short metacarpals (present) , severe mental retardation (present) , seizures at age 8 (absent) , aggression (absent) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: caucasian
Geographic origin: Brazil
Comment on evidence:
(absent at age 8); (absent)
Testing laboratory: Sabin Medicina Diagnóstica
Date variant was reported to submitter: 2018-04-06
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
|
UniProtKB/Swiss-Prot
Accession: SCV000091241.1
First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013 |
|
Comment:
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22366787, 35811451, 24090879)
Comment:
PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls PM1: Located in a mutational hot spot and/or critical and well-established functional domain PM2: Absent from controls (or at extremely low frequency if recessive) from ExAC, 1000Genomas, A3raM, TOPMED, and population databases. PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (p.R1105H, p.R1105C) (Sousa, Hennekam; Nicolaides-Baraitser Syndrome International Consortium, 2014). PM6: variant described as de novo, without confirmatory maternity and paternity analysis. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product [CADD = 34.0].
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
ClinVar contains an entry for this variant (Variation ID: 68770). 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. This variant disrupts the p.Arg1105 amino acid residue in SMARCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366787). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA2 protein function. This missense change has been observed in individuals with Nicolaides-Baraitser syndrome (PMID: 22366787; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1105 of the SMARCA2 protein (p.Arg1105Pro).
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22366787, 35811451, 24090879)
Comment:
PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls PM1: Located in a mutational hot spot and/or critical and well-established functional domain PM2: Absent from controls (or at extremely low frequency if recessive) from ExAC, 1000Genomas, A3raM, TOPMED, and population databases. PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (p.R1105H, p.R1105C) (Sousa, Hennekam; Nicolaides-Baraitser Syndrome International Consortium, 2014). PM6: variant described as de novo, without confirmatory maternity and paternity analysis. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product [CADD = 34.0].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. | Van Houdt JK | Nature genetics | 2012 | PMID: 22366787 |
| - | - | - | - | DOI: 10.1002/ajmg.c.31409 |
Text-mined citations for rs281875197 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.