NM_000368.5(TSC1):c.664-15A>G AND Tuberous sclerosis 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 4, 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:: RCV001257304.7

Allele description [Variation Report for NM_000368.5(TSC1):c.664-15A>G]

NM_000368.5(TSC1):c.664-15A>G

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.664-15A>G

HGVS:

NC_000009.12:g.132921451T>C
NG_012386.1:g.28183A>G
NM_000368.5:c.664-15A>GMANE SELECT
NM_001162426.2:c.664-15A>G
NM_001162427.2:c.511-15A>G
NM_001362177.2:c.301-15A>G
LRG_486t1:c.664-15A>G
LRG_486:g.28183A>G
NC_000009.11:g.135796838T>C
NC_000009.11:g.135796838T>C
NM_000368.3:c.664-15A>G
NM_000368.4:c.664-15A>G
p.(=)

Links:

Tuberous sclerosis database (TSC1): TSC1_00035; dbSNP: rs118203422

NCBI 1000 Genomes Browser:

rs118203422

Molecular consequence:

NM_000368.5:c.664-15A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001162426.2:c.664-15A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001162427.2:c.511-15A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001362177.2:c.301-15A>G - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

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

Recent activity

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Limia zonata voucher ULV:ZRSJ6 cytochrome b gene, partial cds; tRNA-Thr and tRNA...
Limia zonata voucher ULV:ZRSJ6 cytochrome b gene, partial cds; tRNA-Thr and tRNA-Pro genes, complete sequence; and D-loop, partial sequence; mitochondrial
gi|1044452533|gb|KX024210.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001433850	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002058871	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002167093	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21520333, 26540169, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433850

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 10, 2020)

germline

clinical testing

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

SCV002058871

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 3, 2022)

germline

clinical testing

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

SCV002167093

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Japanese	germline	yes	1	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

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21520333

See all PubMed Citations (4)

Details of each submission

From Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, SCV001433850.1

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

From 3billion, SCV002058871.1

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

Description

The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049079).It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (3billion dataset, PS2_S). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

#	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, SCV002167093.3

#	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 falls in intron 7 of the TSC1 gene. It does not directly change the encoded amino acid sequence of the TSC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 21520333, 26540169). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49079). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

#	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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