NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Apr 1, 2024
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:: RCV000414340.27

Allele description

NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln)

Gene:

TSC2:TSC complex subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln)

HGVS:

NC_000016.10:g.2070571G>A
NG_005895.1:g.26266G>A
NM_000548.5:c.1832G>AMANE SELECT
NM_001077183.3:c.1832G>A
NM_001114382.3:c.1832G>A
NM_001318827.2:c.1721G>A
NM_001318829.2:c.1685G>A
NM_001318831.2:c.1232G>A
NM_001318832.2:c.1865G>A
NM_001363528.2:c.1832G>A
NM_001370404.1:c.1832G>A
NM_001370405.1:c.1832G>A
NM_021055.3:c.1832G>A
NP_000539.2:p.Arg611Gln
NP_001070651.1:p.Arg611Gln
NP_001107854.1:p.Arg611Gln
NP_001305756.1:p.Arg574Gln
NP_001305758.1:p.Arg562Gln
NP_001305760.1:p.Arg411Gln
NP_001305761.1:p.Arg622Gln
NP_001350457.1:p.Arg611Gln
NP_001357333.1:p.Arg611Gln
NP_001357334.1:p.Arg611Gln
NP_066399.2:p.Arg611Gln
LRG_487t1:c.1832G>A
LRG_487:g.26266G>A
NC_000016.9:g.2120572G>A
NM_000548.2:c.1832G>A
NM_000548.3:c.1832G>A
P49815:p.Arg611Gln
p.(Arg611Gln)

Protein change:

R411Q; ARG611GLN

Links:

Tuberous sclerosis database (TSC2): TSC2_00105; UniProtKB: P49815#VAR_005650; OMIM: 191092.0006; dbSNP: rs28934872

NCBI 1000 Genomes Browser:

rs28934872

Molecular consequence:

NM_000548.5:c.1832G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.1832G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.1832G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.1685G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.1232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.1865G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.1832G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.1832G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.1832G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.1832G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000491001	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 9, 2021)	germline	clinical testing	Citation Link,
SCV000615886	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 14, 2019)	unknown	clinical testing	PubMed (23) [See all records that cite these PMIDs] 10205261, 10570911, 10823953, 11741832, 15483652, 15595939, 15963462, 16032769, 16114042, 16464865, 17120248, 17304050, 18302728, 18308511, 18854862, 21309039, 21332470, 23006675, 26703369, 29476190, 9463313, 9829910, 26467025
SCV001334512	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2024)	germline	clinical testing	Citation Link,
SCV003799245	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Apr 18, 2022)	germline	clinical testing	Citation Link,
SCV003802810	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020)	Pathogenic (Sep 15, 2022)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 32555378, 15963462, 9463313, 22867869, 15595939 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.

Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP.

Am J Hum Genet. 1999 May;64(5):1305-15. Review.

PubMed [citation]

PMID:: 10205261
PMCID:: PMC1377866

Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex.

Zhang H, Nanba E, Yamamoto T, Ninomiya H, Ohno K, Mizuguchi M, Takeshita K.

J Hum Genet. 1999;44(6):391-6. Erratum in: J Hum Genet 2000;45(4):269.

PubMed [citation]

PMID:: 10570911

See all PubMed Citations (25)

Details of each submission

From GeneDx, SCV000491001.3

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

Description

Functional studies indicate that R611Q disrupts the TSC1-TSC2 complex (Nellist et al., 2001; Nellist et al., 2005; Hoogeveen-Westerveld et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 31447099, 27542907, 22867869, 15483652, 15798777, 11741832, 27216612, 26703369, 27406250, 29632054, 29129521, 29308833, 29476190, 16032769, 30293248, 31083211, 32555378, 31799751, 32340510, 32313033, 18466115, 30787465, 9463313, 32211034, 21309039)

#	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 Athena Diagnostics, SCV000615886.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (23)

Description

Not found in the total gnomAD dataset, and the data is high quality. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. One de novo case with parental identity confirmed plus 1 unconfirmed case.

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

From CeGaT Center for Human Genetics Tuebingen, SCV001334512.20

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

Description

TSC2: PM6:Strong, PM2, PM5, PS3:Moderate, PS4:Moderate, PP4

#	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		2	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799245.2

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

Description

The TSC2 c.1832G>A; p.Arg611Gln variant (rs28934872) is described in the literature in several individuals with a clinical diagnosis of tuberous sclerosis complex, including the variant occurring de novo in at least three individuals (Babol-Pokora 2021, Reyna-Fabian 2020, Suspitsin 2018). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 12397) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 611 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.893). Functional studies indicate the variant disrupts the interaction with hamartin and inhibits phosphorylation (Hoogeveen-Westerveld 2011, Nellist 2005). Based on available information, this variant is classified as pathogenic. References: Babol-Pokora K et al. A multistep approach to the genotype-phenotype analysis of Polish patients with tuberous sclerosis complex. Eur J Med Genet. 2021 Oct;64(10):104309. PMID: 34403804. Hoogeveen-Westerveld M et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Apr;32(4):424-35. PMID: 21309039. Nellist M et al. Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur J Hum Genet. 2005 Jan;13(1):59-68. PMID: 15483652. Reyna-Fabian ME et al. First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants. Sci Rep. 2020 Apr 20;10(1):6589. PMID: 32313033. Suspitsin EN et al. Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis. J Hum Genet. 2018 May;63(5):597-604. PMID: 29476190.

#	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

From Illumina Laboratory Services, Illumina, SCV003802810.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The TSC2 c.1832G>A (p.Arg611Gln) missense variant results in the substitution of arginine at amino acid position 611 with glutamine. Across a selection of available literature, the c.1832G>A variant has been reported in at least 17 individuals with tuberous sclerosis complex, with several described as occurring de novo (PMID: 9463313; PMID: 15595939; PMID: 22867869; PMID: 32555378). Another variant at the same amino acid position, c.1831C>T (p.Arg611Trp), has been reported in a heterozygous state in at least six individuals with tuberous sclerosis complex (PMID: 15595939; PMID: 22867869). The c.1832G>A variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional analysis using mass spectrometry and coimmunoprecipitation determined the c.1832G>A variant is associated with loss of phosphorylation and is inactivated due to protein mis-folding (PMID: 15963462). This variant was identified in a de novo state. Based on the available evidence, the c.1832G>A (p.Arg611Gln) variant is classified as pathogenic for tuberous sclerosis complex.

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

Last Updated: Jun 2, 2024

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