NM_003073.5(SMARCB1):c.1121G>A (p.Arg374Gln) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 28, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000412754.3

Allele description [Variation Report for NM_003073.5(SMARCB1):c.1121G>A (p.Arg374Gln)]

NM_003073.5(SMARCB1):c.1121G>A (p.Arg374Gln)

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.1121G>A (p.Arg374Gln)
HGVS:
  • NC_000022.11:g.23834143G>A
  • NG_009303.1:g.52181G>A
  • NM_001007468.3:c.1094G>A
  • NM_001317946.2:c.1148G>A
  • NM_001362877.2:c.1175G>A
  • NM_003073.5:c.1121G>AMANE SELECT
  • NP_001007469.1:p.Arg365Gln
  • NP_001304875.1:p.Arg383Gln
  • NP_001349806.1:p.Arg392Gln
  • NP_003064.2:p.Arg374Gln
  • LRG_520t1:c.1121G>A
  • LRG_520:g.52181G>A
  • NC_000022.10:g.24176330G>A
  • NM_003073.3:c.1121G>A
Protein change:
R365Q
Links:
dbSNP: rs1057517825
NCBI 1000 Genomes Browser:
rs1057517825
Molecular consequence:
  • NM_001007468.3:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317946.2:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362877.2:c.1175G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003073.5:c.1121G>A - 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
SCV000490818GeneDxcriteria provided, single submitter
Pathogenic
(Oct 28, 2021)
germlineclinical testing

Citation Link,

SCV000940629Invitaecriteria provided, single submitter
Likely pathogenic
(Nov 28, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis.

Gossai N, Biegel JA, Messiaen L, Berry SA, Moertel CL.

Am J Med Genet A. 2015 Dec;167A(12):3186-91. doi: 10.1002/ajmg.a.37356. Epub 2015 Sep 14.

PubMed [citation]
PMID:
26364901

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, Bögershausen N, Beleggia F, Steiner-Haldenstätt S, Pohl E, Li Y, Milz E, Martin M, Thiele H, Altmüller J, Alanay Y, Kayserili H, Klein-Hitpass L, Böhringer S, Wollstein A, Albrecht B, Boduroglu K, Caliebe A, Chrzanowska K, Cogulu O, Cristofoli F, Czeschik JC, et al.

Hum Mol Genet. 2013 Dec 20;22(25):5121-35. doi: 10.1093/hmg/ddt366. Epub 2013 Aug 1.

PubMed [citation]
PMID:
23906836
See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000490818.2

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

Description

Reported in an adult male in published literature with Coffin-Siris syndrome and schwannomatosis (Gossai et al., 2015); 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: 11104031, 23091298, 23525077, 31216405, 23906836, 31273213, 26364901)

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

From Invitae, SCV000940629.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces arginine with glutamine at codon 374 of the SMARCB1 protein (p.Arg374Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Coffin-Siris syndrome (PMID: 23906836, 26364901, Invitae). ClinVar contains an entry for this variant (Variation ID: 372511). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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

Last Updated: Nov 6, 2021

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