NM_003072.5(SMARCA4):c.4201G>A (p.Glu1401Lys) AND Rhabdoid tumor predisposition syndrome 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 15, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000557847.9

Allele description [Variation Report for NM_003072.5(SMARCA4):c.4201G>A (p.Glu1401Lys)]

NM_003072.5(SMARCA4):c.4201G>A (p.Glu1401Lys)

Gene:

SMARCA4:SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_003072.5(SMARCA4):c.4201G>A (p.Glu1401Lys)

HGVS:

NC_000019.10:g.11041337G>A
NG_011556.3:g.85406G>A
NM_001128844.3:c.4201G>A
NM_001128845.2:c.4111G>A
NM_001128846.2:c.4111G>A
NM_001128847.4:c.4102G>A
NM_001128848.2:c.4102G>A
NM_001128849.3:c.4297G>A
NM_001374457.1:c.4102G>A
NM_001387283.1:c.4297G>A
NM_003072.5:c.4201G>AMANE SELECT
NP_001122316.1:p.Glu1401Lys
NP_001122317.1:p.Glu1371Lys
NP_001122318.1:p.Glu1371Lys
NP_001122319.1:p.Glu1368Lys
NP_001122320.1:p.Glu1368Lys
NP_001122321.1:p.Glu1433Lys
NP_001361386.1:p.Glu1368Lys
NP_001374212.1:p.Glu1433Lys
NP_003063.2:p.Glu1401Lys
LRG_878t1:c.4201G>A
LRG_878:g.85406G>A
LRG_878p1:p.Glu1401Lys
NC_000019.9:g.11152013G>A
NG_011556.2:g.85416G>A
NM_001128849.1:c.4297G>A
NR_164683.1:n.4591G>A

Protein change:

E1368K

Links:

dbSNP: rs756924224

NCBI 1000 Genomes Browser:

rs756924224

Molecular consequence:

NM_001128844.3:c.4201G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128845.2:c.4111G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128846.2:c.4111G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128847.4:c.4102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128848.2:c.4102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001128849.3:c.4297G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374457.1:c.4102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001387283.1:c.4297G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003072.5:c.4201G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_164683.1:n.4591G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Rhabdoid tumor predisposition syndrome 2 (RTPS2)
Identifiers:: MONDO: MONDO:0013224; MedGen: C2750074; Orphanet: 231108; Orphanet: 69077; OMIM: 613325

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000648102	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30973214, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000648102

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 15, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Retinal dystrophy in an individual carrying a de novo missense variant of SMARCA4.

Cappuccio G, Brunetti-Pierri R, Torella A, Pinelli M, Castello R, Casari G, Nigro V, Banfi S, Simonelli F; TUDP., Brunetti-Pierri N.

Mol Genet Genomic Med. 2019 Jun;7(6):e682. doi: 10.1002/mgg3.682. Epub 2019 Apr 11.

PubMed [citation]

PMID:: 30973214
PMCID:: PMC6565552

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000648102.6

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1433 of the SMARCA4 protein (p.Glu1433Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 30973214). ClinVar contains an entry for this variant (Variation ID: 470393). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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