NM_003073.5(SMARCB1):c.158G>T (p.Arg53Leu) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: May 11, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000490024.4

Allele description [Variation Report for NM_003073.5(SMARCB1):c.158G>T (p.Arg53Leu)]

NM_003073.5(SMARCB1):c.158G>T (p.Arg53Leu)

Gene:
SMARCB1:SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q11.23
Genomic location:
Preferred name:
NM_003073.5(SMARCB1):c.158G>T (p.Arg53Leu)
HGVS:
  • NC_000022.11:g.23791820G>T
  • NG_009303.1:g.9858G>T
  • NM_001007468.3:c.158G>T
  • NM_001317946.2:c.158G>T
  • NM_001362877.2:c.158G>T
  • NM_003073.5:c.158G>TMANE SELECT
  • NP_001007469.1:p.Arg53Leu
  • NP_001304875.1:p.Arg53Leu
  • NP_001349806.1:p.Arg53Leu
  • NP_003064.2:p.Arg53Leu
  • LRG_520t1:c.158G>T
  • LRG_520:g.9858G>T
  • NC_000022.10:g.24134007G>T
  • NM_001007468.2:c.158G>T
  • NM_003073.3:c.158G>T
Protein change:
R53L
Links:
dbSNP: rs779769475
NCBI 1000 Genomes Browser:
rs779769475
Molecular consequence:
  • NM_001007468.3:c.158G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317946.2:c.158G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362877.2:c.158G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003073.5:c.158G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000551560Invitaecriteria provided, single submitter
Uncertain significance
(May 11, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000577245GeneDxcriteria provided, single submitter
Pathogenic
(Nov 19, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis.

Boyd C, Smith MJ, Kluwe L, Balogh A, Maccollin M, Plotkin SR.

Clin Genet. 2008 Oct;74(4):358-66. doi: 10.1111/j.1399-0004.2008.01060.x. Epub 2008 Jul 21.

PubMed [citation]
PMID:
18647326

Expression of SMARCB1 (INI1) mutations in familial schwannomatosis.

Smith MJ, Walker JA, Shen Y, Stemmer-Rachamimov A, Gusella JF, Plotkin SR.

Hum Mol Genet. 2012 Dec 15;21(24):5239-45. doi: 10.1093/hmg/dds370. Epub 2012 Sep 4.

PubMed [citation]
PMID:
22949514
PMCID:
PMC3510754
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000551560.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with leucine at codon 53 of the SMARCB1 protein (p.Arg53Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with schwannomatosis in five individuals in two unrelated families. All analyzed tumors displayed loss of heterozygosity of the wild-type allele (PMID: 18647326). An experimental study has reported that this variant does not impact the capability of SMARCB1 to suppress cyclin D1 activity in cultured cells (PMID: 22949514). However, structural analysis of the SMARCB1 protein showed that this residue is located on the surface of the protein-DNA interaction. Unsuccessful attempts to express SMARCB1 carrying this variant suggested that the loss of this interaction destabilizes the fold of the domain (PMID: 26073604). The clinical significance of these findings is uncertain. In summary, this variant is a rare missense change that is absent in the population and segregates with disease in two families. However, whether or not this variant disrupts SMARCB1 function remains unknown. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV000577245.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The R53L variant has been reported previously in blood and tumor samples from two unrelated individuals who met criteria for 'definitive' or 'presumptive' schwannomatosis and was found to segregate in other affected family members (Boyd et al., 2008). In one of the families, a somatic variant in NF2 was also identified in the tumor specimen (Boyd et al., 2008). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R53L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within a DNA binding domain where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown R53L fails to rescue SMARCB1 null Drosophila specimens (Walker et al., 2013). In summary, we consider this variant to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 12, 2021

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