NM_000368.5(TSC1):c.2391G>T (p.Gln797His) AND Tuberous sclerosis 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 4, 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:: RCV003876690.1

Allele description [Variation Report for NM_000368.5(TSC1):c.2391G>T (p.Gln797His)]

NM_000368.5(TSC1):c.2391G>T (p.Gln797His)

Gene:

TSC1:TSC complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.13

Genomic location:

Preferred name:

NM_000368.5(TSC1):c.2391G>T (p.Gln797His)

HGVS:

NC_000009.12:g.132902605C>A
NG_012386.1:g.47029G>T
NM_000368.5:c.2391G>TMANE SELECT
NM_001162426.2:c.2388G>T
NM_001162427.2:c.2238G>T
NM_001362177.2:c.2028G>T
NM_001406592.1:c.2391G>T
NM_001406593.1:c.2391G>T
NM_001406594.1:c.2391G>T
NM_001406595.1:c.2391G>T
NM_001406596.1:c.2391G>T
NM_001406597.1:c.2388G>T
NM_001406598.1:c.2388G>T
NM_001406599.1:c.2388G>T
NM_001406600.1:c.2388G>T
NM_001406601.1:c.2376G>T
NM_001406602.1:c.2376G>T
NM_001406603.1:c.2373G>T
NM_001406604.1:c.2373G>T
NM_001406605.1:c.2391G>T
NM_001406606.1:c.2391G>T
NM_001406607.1:c.2391G>T
NM_001406608.1:c.2388G>T
NM_001406609.1:c.2388G>T
NM_001406610.1:c.2238G>T
NM_001406611.1:c.2235G>T
NM_001406612.1:c.2235G>T
NM_001406613.1:c.2235G>T
NM_001406614.1:c.2028G>T
NM_001406615.1:c.2028G>T
NM_001406616.1:c.2028G>T
NM_001406617.1:c.2028G>T
NM_001406618.1:c.2028G>T
NM_001406619.1:c.2028G>T
NM_001406620.1:c.2025G>T
NM_001406621.1:c.2025G>T
NM_001406622.1:c.2025G>T
NM_001406623.1:c.2025G>T
NM_001406624.1:c.2028G>T
NM_001406625.1:c.2025G>T
NM_001406626.1:c.1440G>T
NM_001406627.1:c.1437G>T
NM_001406628.1:c.1437G>T
NM_001406629.1:c.1338G>T
NM_001406630.1:c.1338G>T
NP_000359.1:p.Gln797His
NP_000359.1:p.Gln797His
NP_000359.1:p.Gln797His
NP_001155898.1:p.Gln796His
NP_001155899.1:p.Gln746His
NP_001349106.1:p.Gln676His
NP_001393521.1:p.Gln797His
NP_001393522.1:p.Gln797His
NP_001393523.1:p.Gln797His
NP_001393524.1:p.Gln797His
NP_001393525.1:p.Gln797His
NP_001393526.1:p.Gln796His
NP_001393527.1:p.Gln796His
NP_001393528.1:p.Gln796His
NP_001393529.1:p.Gln796His
NP_001393530.1:p.Gln792His
NP_001393531.1:p.Gln792His
NP_001393532.1:p.Gln791His
NP_001393533.1:p.Gln791His
NP_001393534.1:p.Gln797His
NP_001393535.1:p.Gln797His
NP_001393536.1:p.Gln797His
NP_001393537.1:p.Gln796His
NP_001393538.1:p.Gln796His
NP_001393539.1:p.Gln746His
NP_001393540.1:p.Gln745His
NP_001393541.1:p.Gln745His
NP_001393542.1:p.Gln745His
NP_001393543.1:p.Gln676His
NP_001393544.1:p.Gln676His
NP_001393545.1:p.Gln676His
NP_001393546.1:p.Gln676His
NP_001393547.1:p.Gln676His
NP_001393548.1:p.Gln676His
NP_001393549.1:p.Gln675His
NP_001393550.1:p.Gln675His
NP_001393551.1:p.Gln675His
NP_001393552.1:p.Gln675His
NP_001393553.1:p.Gln676His
NP_001393554.1:p.Gln675His
NP_001393555.1:p.Gln480His
NP_001393556.1:p.Gln479His
NP_001393557.1:p.Gln479His
NP_001393558.1:p.Gln446His
NP_001393559.1:p.Gln446His
LRG_486t1:c.2391G>T
LRG_486:g.47029G>T
LRG_486p1:p.Gln797His
NC_000009.11:g.135777992C>A
NM_000368.3:c.2391G>T
NM_000368.4:c.2391G>T
NR_176214.1:n.2441G>T
NR_176215.1:n.2608G>T
NR_176216.1:n.2475G>T
NR_176217.1:n.2605G>T
NR_176218.1:n.2604G>T

Protein change:

Q446H

Molecular consequence:

NM_000368.5:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001162426.2:c.2388G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001162427.2:c.2238G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001362177.2:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406592.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406593.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406594.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406595.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406596.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406597.1:c.2388G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406598.1:c.2388G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406599.1:c.2388G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406600.1:c.2388G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406601.1:c.2376G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406602.1:c.2376G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406603.1:c.2373G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406604.1:c.2373G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406605.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406606.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406607.1:c.2391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406608.1:c.2388G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406609.1:c.2388G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406610.1:c.2238G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406611.1:c.2235G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406612.1:c.2235G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406613.1:c.2235G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406614.1:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406615.1:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406616.1:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406617.1:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406618.1:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406619.1:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406620.1:c.2025G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406621.1:c.2025G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406622.1:c.2025G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406623.1:c.2025G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406624.1:c.2028G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406625.1:c.2025G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406626.1:c.1440G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406627.1:c.1437G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406628.1:c.1437G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406629.1:c.1338G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406630.1:c.1338G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_176214.1:n.2441G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176215.1:n.2608G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176216.1:n.2475G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176217.1:n.2605G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176218.1:n.2604G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Tuberous sclerosis 1 (TSC1)
Identifiers:: MONDO: MONDO:0008612; MedGen: C1854465; Orphanet: 805; OMIM: 191100

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telomerase regulation-associated protein [Homo sapiens]
telomerase regulation-associated protein [Homo sapiens]
gi|10444417|gb|AAG17902.1|AF297709_

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004681734	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004681734

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 2023)

germline

clinical testing

PubMed (3)
[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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004681734.1

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

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 797 of the TSC1 protein (p.Gln797His). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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: Jun 2, 2024

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