VCV000030017.11 - ClinVar

NM_003070.5(SMARCA2):c.3602C>T (p.Ala1201Val)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

2 out of 6 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Functional data are available for this variant

Variant Details

Identifiers

NM_003070.5(SMARCA2):c.3602C>T (p.Ala1201Val)

Variation ID: 30017 Accession: VCV000030017.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p24.3 9: 2115967 (GRCh38) [ NCBI UCSC ] 9: 2115967 (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	Apr 4, 2013	Jul 5, 2025	Jun 25, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_003070.5:c.3602C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003061.3:p.Ala1201Val	missense
NM_001289396.2:c.3602C>T	NP_001276325.1:p.Ala1201Val	missense
NM_001289397.2:c.3428C>T	NP_001276326.1:p.Ala1143Val	missense
NM_139045.4:c.3602C>T	NP_620614.2:p.Ala1201Val	missense
NC_000009.12:g.2115967C>T
NC_000009.11:g.2115967C>T
NG_032162.2:g.140678C>T
LRG_882:g.140678C>T
LRG_882t1:c.3602C>T	LRG_882p1:p.Ala1201Val
	P51531:p.Ala1201Val

... more HGVS ... less HGVS

Protein change

A1201V, A1143V

Other names

NC_000009.11:g.2115967C>T

Canonical SPDI

NC_000009.12:2115966:C:T

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: CA211277 UniProtKB: P51531#VAR_068205 UniProtKB/Swiss-Prot: VAR_068205 OMIM: 600014.0010 dbSNP: rs281875189 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.
SMARCA2		No evidence available	No evidence available	GRCh38 GRCh37	1464	1646

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 (2)	criteria provided, single submitter	Jun 25, 2025	RCV000059680.7
Nicolaides-Baraitser syndrome	Pathogenic (1)	no assertion criteria provided	Feb 26, 2012	RCV000022917.4
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Sep 10, 2020	RCV001260811.2
Hirsutism Intellectual disability	Likely pathogenic (1)	no assertion criteria provided	Sep 26, 2019	RCV001261297.3

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.	Expand all rows Collapse all rows 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 (Jun 25, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV000329680.9 First in ClinVar: Dec 06, 2016 Last updated: Jul 05, 2025	Comment: show RNA studies demonstrate a damaging effect: abnormal splicing with exon 25 deleted (PMID: 38113761); Not observed at significant frequency 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: 22366787, 25169058, 24090879, 30459321, 35811451, 35982159, 35904121, 33057194, 38113761) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Sep 10, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Intellectual disability	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001437906.1 First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020	Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Zygosity: Single Heterozygote Method: targeted next-gen sequencing

Pathogenic (Feb 26, 2012) N Not contributing to aggregate classification	no assertion criteria provided	NICOLAIDES-BARAITSER SYNDROME	OMIM Accession: SCV000044208.2 First in ClinVar: Apr 04, 2013 Last updated: May 06, 2021	Publications: PubMed (1) PubMed: 22366787 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In 3 unrelated individuals with Nicolaides-Baraitser syndrome (NCBRS; 601358), Van Houdt et al. (2012) identified a heterozygous C-to-T transition at nucleotide 3602 in exon 25 … (more) In 3 unrelated individuals with Nicolaides-Baraitser syndrome (NCBRS; 601358), Van Houdt et al. (2012) identified a heterozygous C-to-T transition at nucleotide 3602 in exon 25 of the SMARCA2 gene, resulting in a ala-to-val substitution at codon 1201 (A1201V). In 2 of the patients the mutation was confirmed to have occurred de novo. The mutation was not seen in 1,300 control exomes. (less)

Likely pathogenic (Sep 26, 2019) N Not contributing to aggregate classification	no assertion criteria provided	Hirsutism intellectual disability	Autoinflammatory diseases unit, CHU de Montpellier Accession: SCV001438106.2 First in ClinVar: Oct 23, 2020 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Sex: female

not provided (-) N Not contributing to aggregate classification	no classification provided	not provided	UniProtKB/Swiss-Prot Accession: SCV000091250.1 First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013	Observation: 1 Collection method: not provided Allele origin: not provided Affected status: not provided Observation 1 Collection method: not provided Allele origin: not provided Affected status: not provided

Comment:

RNA studies demonstrate a damaging effect: abnormal splicing with exon 25 deleted (PMID: 38113761); Not observed at significant frequency 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: 22366787, 25169058, 24090879, 30459321, 35811451, 35982159, 35904121, 33057194, 38113761)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.	Van Houdt JK	Nature genetics	2012	PMID: 22366787

Submissions - Functional Data

functionally abnormal -- skipped exon

assessed by RNAseq

Result:

junction spanning - exon skipping (p=0.0484)

Modifies an exonic cryptic donor site at NC_000009.11:g.2115966 from -0.35 to 6.68 bits. Significant p-values: junction spanning - exon skipping (3 reads, p=0.0484). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006729101.1

Submitted: 2025-10-17

Assay description:

In the sample (ICGC_DO46841), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Nonpapillary renal cell carcinoma
Transcript, protein change: NM_003070.5:c.3602C>T, A1201V
Molecular phenotype measured: splicing
Cell line: ICGC_DO46841
Tissue: Renal Cell Cancer (RECA-EU)
Collection method: in vitro
Species: human
Number of controls: 134

Text-mined citations for rs281875189 ...

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 02, 2025

ClinVar Genomic variation as it relates to human health

NM_003070.5(SMARCA2):c.3602C>T (p.Ala1201Val)

Functional data are available for this variant

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Submissions - Functional Data

Text-mined citations for rs281875189 ...