NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro) AND not provided

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Oct 31, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000059671.11

Allele description [Variation Report for NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro)]

NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro)

Gene:

SMARCA2:SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p24.3

Genomic location:

Preferred name:

NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro)

HGVS:

NC_000009.12:g.2110275G>C
NG_032162.2:g.134986G>C
NM_001289396.2:c.3314G>C
NM_001289397.2:c.3140G>C
NM_003070.5:c.3314G>CMANE SELECT
NM_139045.4:c.3314G>C
NP_001276325.1:p.Arg1105Pro
NP_001276325.1:p.Arg1105Pro
NP_001276326.1:p.Arg1047Pro
NP_003061.3:p.Arg1105Pro
NP_620614.2:p.Arg1105Pro
LRG_882t1:c.3314G>C
LRG_882:g.134986G>C
LRG_882p1:p.Arg1105Pro
NC_000009.11:g.2110275G>C
NM_001289396.1:c.3314G>C
NM_003070.3:c.3314G>C
P51531:p.Arg1105Pro

Protein change:

R1047P

Links:

UniProtKB: P51531#VAR_068196; UniProtKB/Swiss-Prot: VAR_068196; dbSNP: rs281875197

NCBI 1000 Genomes Browser:

rs281875197

Molecular consequence:

NM_001289396.2:c.3314G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289397.2:c.3140G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003070.5:c.3314G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139045.4:c.3314G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000091241	UniProtKB/Swiss-Prot	no classification provided	not provided	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV004170082	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 31, 2023)	germline	clinical testing	Citation Link,
SCV004295974	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22366787, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000091241

UniProtKB/Swiss-Prot

no classification provided

not provided

PubMed (1)
[See all records that cite this PMID]

SCV004170082

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Oct 31, 2023)

germline

clinical testing

Citation Link,

SCV004295974

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 17, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.

Van Houdt JK, Nowakowska BA, Sousa SB, van Schaik BD, Seuntjens E, Avonce N, Sifrim A, Abdul-Rahman OA, van den Boogaard MJ, Bottani A, Castori M, Cormier-Daire V, Deardorff MA, Filges I, Fryer A, Fryns JP, Gana S, Garavelli L, Gillessen-Kaesbach G, Hall BD, Horn D, Huylebroeck D, et al.

Nat Genet. 2012 Feb 26;44(4):445-9, S1. doi: 10.1038/ng.1105.

PubMed [citation]

PMID:: 22366787

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From UniProtKB/Swiss-Prot, SCV000091241.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV004170082.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295974.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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