NM_000548.5(TSC2):c.1678G>A (p.Val560Met) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 20, 2023
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:: RCV000782250.5

Allele description [Variation Report for NM_000548.5(TSC2):c.1678G>A (p.Val560Met)]

NM_000548.5(TSC2):c.1678G>A (p.Val560Met)

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.1678G>A (p.Val560Met)

HGVS:

NC_000016.10:g.2065597G>A
NG_005895.1:g.21292G>A
NM_000548.5:c.1678G>AMANE SELECT
NM_001077183.3:c.1678G>A
NM_001114382.3:c.1678G>A
NM_001318827.2:c.1567G>A
NM_001318829.2:c.1531G>A
NM_001318831.2:c.1078G>A
NM_001318832.2:c.1711G>A
NM_001363528.2:c.1678G>A
NM_001370404.1:c.1678G>A
NM_001370405.1:c.1678G>A
NM_021055.3:c.1678G>A
NP_000539.2:p.Val560Met
NP_001070651.1:p.Val560Met
NP_001107854.1:p.Val560Met
NP_001305756.1:p.Val523Met
NP_001305758.1:p.Val511Met
NP_001305760.1:p.Val360Met
NP_001305761.1:p.Val571Met
NP_001350457.1:p.Val560Met
NP_001357333.1:p.Val560Met
NP_001357334.1:p.Val560Met
NP_066399.2:p.Val560Met
LRG_487t1:c.1678G>A
LRG_487:g.21292G>A
NC_000016.9:g.2115598G>A
NM_000548.3:c.1678G>A
p.(Val560Met)

Protein change:

V360M

Links:

Tuberous sclerosis database (TSC2): TSC2_02018; dbSNP: rs141631268

NCBI 1000 Genomes Browser:

rs141631268

Molecular consequence:

NM_000548.5:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.1567G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.1531G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.1078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.1711G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.1678G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000920740	Gharavi Laboratory, Columbia University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001549038	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV003845501	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 20, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000920740

Gharavi Laboratory, Columbia University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 16, 2018)

germline

research

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

SCV001549038

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV003845501

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Feb 20, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Gharavi Laboratory, Columbia University, SCV000920740.1

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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001549038.1

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

Description

The TSC2 p.V560M variant was not identified in the literature but was identified in dbSNP (ID: rs141631268) and ClinVar (classified as uncertain significance by Fulgent Genetics, Ambry Genetics and two other submitters; and as likely benign by Invitae). The variant was identified in control databases in 3 of 250734 chromosomes at a frequency of 0.00001196 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.V560 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#	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

From GeneDx, SCV003845501.1

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies report this variant is associated with normal TSC2 protein levels, a mild reduction in TSC1 protein levels that did not reach statistical significance, and a mild increase in TORC1 activity that did not reach statistical significance (Hoogeveen-Westerveld et al., 2011); This variant is associated with the following publications: (PMID: 24055113, 21309039, 25525159, 25637381)

#	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

Last Updated: Feb 28, 2024

ClinVar

Relating variation to medicine