VCV000265393.27 - ClinVar

NM_003073.5(SMARCB1):c.1096C>T (p.Arg366Cys)

Germline

Classification

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)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003073.5(SMARCB1):c.1096C>T (p.Arg366Cys)

Variation ID: 265393 Accession: VCV000265393.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q11.23 22: 23833681 (GRCh38) [ NCBI UCSC ] 22: 24175868 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 10, 2016	Oct 20, 2024	May 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003073.5:c.1096C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003064.2:p.Arg366Cys	missense
NM_001007468.3:c.1069C>T	NP_001007469.1:p.Arg357Cys	missense
NM_001317946.2:c.1123C>T	NP_001304875.1:p.Arg375Cys	missense
NM_001362877.2:c.1150C>T	NP_001349806.1:p.Arg384Cys	missense
NC_000022.11:g.23833681C>T
NC_000022.10:g.24175868C>T
NG_009303.1:g.51719C>T
LRG_520:g.51719C>T
LRG_520t1:c.1096C>T
	Q12824:p.Arg366Cys

... more HGVS ... less HGVS

Protein change

R366C, R357C, R375C, R384C

Other names

Canonical SPDI

NC_000022.11:23833680:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10588715 UniProtKB: Q12824#VAR_076934 dbSNP: rs886039520 VarSome

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
Gene	OMIM	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.
SMARCB1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	1074	1213

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.
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 20, 2023	RCV000255465.23
Intellectual disability, autosomal dominant 15	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 10, 2021	RCV001782753.7

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.
Pathogenic (May 20, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322233.8 First in ClinVar: Oct 10, 2016 Last updated: Jun 03, 2023	Comment: Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is … (more) Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25249037, 23906836, 25168959, 30123105, 28824374, 31759698, 27535533) (less)
Likely pathogenic (Apr 10, 2021)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Intellectual disability, autosomal dominant 15 Affected status: unknown Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV002099059.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022	Comment: The c.1096C>T (p.Arg366Cys) variant in exon 8 of 9 of SMARCB1 has been reported at least twice in in the literature in affected individuals [PMID: … (more) The c.1096C>T (p.Arg366Cys) variant in exon 8 of 9 of SMARCB1 has been reported at least twice in in the literature in affected individuals [PMID: 23906836; PMID: 30459321]. This variant is absent in gnomADv3 suggesting it is not a common benign variant in the populations represented in this database and has been reported once in Clinvar as Pathogenic [Variation ID:265393]. In silico predictors suggest this variant is Damaging (Provean score: -5.94, SIFT score: 0.003). Given the evidence regarding its pathogenicity, the c.1096C>T (p.Arg366Cys) variant identified in the SMARCB1 gene is classified as Likely Pathogenic. (less) Clinical Features: Global developmental delay (present) , Intellectual disability (present) , Congenital nystagmus (present) , Ventricular septal defect (present) , Hypotonia (present) , Hypertonia (present) , Failure … (more) Global developmental delay (present) , Intellectual disability (present) , Congenital nystagmus (present) , Ventricular septal defect (present) , Hypotonia (present) , Hypertonia (present) , Failure to thrive (present) , Congenital laryngomalacia (present) (less) Secondary finding: no
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 15 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Suma Genomics Accession: SCV002543805.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Likely pathogenic (Nov 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002289214.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 23906836 Comment: 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 … (more) 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. 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 SMARCB1 protein function. ClinVar contains an entry for this variant (Variation ID: 265393). This missense change has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 23906836). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 366 of the SMARCB1 protein (p.Arg366Cys). (less)
Likely pathogenic (Dec 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002821110.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: SMARCB1: PM2, PS4:Moderate, PP2, PP3, PS3:Supporting Number of individuals with the variant: 1

Comment:

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25249037, 23906836, 25168959, 30123105, 28824374, 31759698, 27535533)

Comment:

The c.1096C>T (p.Arg366Cys) variant in exon 8 of 9 of SMARCB1 has been reported at least twice in in the literature in affected individuals [PMID: 23906836; PMID: 30459321]. This variant is absent in gnomADv3 suggesting it is not a common benign variant in the populations represented in this database and has been reported once in Clinvar as Pathogenic [Variation ID:265393]. In silico predictors suggest this variant is Damaging (Provean score: -5.94, SIFT score: 0.003). Given the evidence regarding its pathogenicity, the c.1096C>T (p.Arg366Cys) variant identified in the SMARCB1 gene is classified as Likely Pathogenic.

Comment:

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. 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 SMARCB1 protein function. ClinVar contains an entry for this variant (Variation ID: 265393). This missense change has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 23906836). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 366 of the SMARCB1 protein (p.Arg366Cys).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.	Wieczorek D	Human molecular genetics	2013	PMID: 23906836

Text-mined citations for rs886039520 ...

These 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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_003073.5(SMARCB1):c.1096C>T (p.Arg366Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886039520 ...