NM_000548.5(TSC2):c.1835T>C (p.Leu612Pro) AND Tuberous sclerosis 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 25, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000761363.12

Allele description [Variation Report for NM_000548.5(TSC2):c.1835T>C (p.Leu612Pro)]

NM_000548.5(TSC2):c.1835T>C (p.Leu612Pro)

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.1835T>C (p.Leu612Pro)

HGVS:

NC_000016.10:g.2070574T>C
NG_005895.1:g.26269T>C
NM_000548.5:c.1835T>CMANE SELECT
NM_001077183.3:c.1835T>C
NM_001114382.3:c.1835T>C
NM_001318827.2:c.1724T>C
NM_001318829.2:c.1688T>C
NM_001318831.2:c.1235T>C
NM_001318832.2:c.1868T>C
NM_001363528.2:c.1835T>C
NM_001370404.1:c.1835T>C
NM_001370405.1:c.1835T>C
NM_021055.3:c.1835T>C
NP_000539.2:p.Leu612Pro
NP_001070651.1:p.Leu612Pro
NP_001107854.1:p.Leu612Pro
NP_001305756.1:p.Leu575Pro
NP_001305758.1:p.Leu563Pro
NP_001305760.1:p.Leu412Pro
NP_001305761.1:p.Leu623Pro
NP_001350457.1:p.Leu612Pro
NP_001357333.1:p.Leu612Pro
NP_001357334.1:p.Leu612Pro
NP_066399.2:p.Leu612Pro
LRG_487t1:c.1835T>C
LRG_487:g.26269T>C
NC_000016.9:g.2120575T>C
NM_000548.3:c.1835T>C

Protein change:

L412P

Links:

dbSNP: rs1567458244

NCBI 1000 Genomes Browser:

rs1567458244

Molecular consequence:

NM_000548.5:c.1835T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.1835T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.1835T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.1724T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.1688T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.1235T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.1868T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.1835T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.1835T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.1835T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.1835T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Tuberous sclerosis 2 (TSC2)
Identifiers:: MONDO: MONDO:0013199; MedGen: C1860707; Orphanet: 805; OMIM: 613254

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000891349	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 6, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25782670, 25741868 Citation Link,
SCV001517990	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 25, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25782670, 31655562, 28492532
SCV002039580	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000891349

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 6, 2018)

germline

clinical testing

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

Citation Link,

SCV001517990

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 25, 2022)

germline

clinical testing

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

SCV002039580

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	no	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

Citations

PubMed

Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2.

Kwiatkowski DJ, Palmer MR, Jozwiak S, Bissler J, Franz D, Segal S, Chen D, Sampson JR.

Eur J Hum Genet. 2015 Dec;23(12):1665-72. doi: 10.1038/ejhg.2015.47. Epub 2015 Mar 18.

PubMed [citation]

PMID:: 25782670
PMCID:: PMC4795200

Decoding of novel missense TSC2 gene variants using in-silico methods.

Sudarshan S, Kumar M, Kaur P, Kumar A, G S, Sapra S, Gulati S, Gupta N, Kabra M, Roy Chowdhury M.

BMC Med Genet. 2019 Oct 26;20(1):164. doi: 10.1186/s12881-019-0891-y.

PubMed [citation]

PMID:: 31655562
PMCID:: PMC6815426

See all PubMed Citations (4)

Details of each submission

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000891349.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001517990.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 623238). This missense change has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 25782670, 31655562). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 612 of the TSC2 protein (p.Leu612Pro).

#	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 Genome-Nilou Lab, SCV002039580.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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