This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 249 of the TSC1 protein (p.Arg249Lys). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 95%. 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.
ClinVar Genomic variation as it relates to human health
NM_000368.5(TSC1):c.746G>A (p.Arg249Lys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
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Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000368.5(TSC1):c.746G>A (p.Arg249Lys)
Variation ID: 2705868 Accession: VCV002705868.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.13 9: 135787836 (GRCh37) [ NCBI UCSC ] 9: 132912449 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 14, 2024 Feb 14, 2024 Dec 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000368.5:c.746G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000359.1:p.Arg249Lys missense NM_001162426.2:c.746G>A NP_001155898.1:p.Arg249Lys missense NM_001162427.2:c.593G>A NP_001155899.1:p.Arg198Lys missense NM_001362177.2:c.383G>A NP_001349106.1:p.Arg128Lys missense NM_001406592.1:c.746G>A NP_001393521.1:p.Arg249Lys missense NM_001406593.1:c.746G>A NP_001393522.1:p.Arg249Lys missense NM_001406594.1:c.746G>A NP_001393523.1:p.Arg249Lys missense NM_001406595.1:c.746G>A NP_001393524.1:p.Arg249Lys missense NM_001406596.1:c.746G>A NP_001393525.1:p.Arg249Lys missense NM_001406597.1:c.746G>A NP_001393526.1:p.Arg249Lys missense NM_001406598.1:c.746G>A NP_001393527.1:p.Arg249Lys missense NM_001406599.1:c.746G>A NP_001393528.1:p.Arg249Lys missense NM_001406600.1:c.746G>A NP_001393529.1:p.Arg249Lys missense NM_001406601.1:c.746G>A NP_001393530.1:p.Arg249Lys missense NM_001406602.1:c.746G>A NP_001393531.1:p.Arg249Lys missense NM_001406603.1:c.746G>A NP_001393532.1:p.Arg249Lys missense NM_001406604.1:c.746G>A NP_001393533.1:p.Arg249Lys missense NM_001406605.1:c.746G>A NP_001393534.1:p.Arg249Lys missense NM_001406606.1:c.746G>A NP_001393535.1:p.Arg249Lys missense NM_001406607.1:c.746G>A NP_001393536.1:p.Arg249Lys missense NM_001406608.1:c.746G>A NP_001393537.1:p.Arg249Lys missense NM_001406609.1:c.746G>A NP_001393538.1:p.Arg249Lys missense NM_001406610.1:c.593G>A NP_001393539.1:p.Arg198Lys missense NM_001406611.1:c.593G>A NP_001393540.1:p.Arg198Lys missense NM_001406612.1:c.593G>A NP_001393541.1:p.Arg198Lys missense NM_001406613.1:c.593G>A NP_001393542.1:p.Arg198Lys missense NM_001406614.1:c.383G>A NP_001393543.1:p.Arg128Lys missense NM_001406615.1:c.383G>A NP_001393544.1:p.Arg128Lys missense NM_001406616.1:c.383G>A NP_001393545.1:p.Arg128Lys missense NM_001406617.1:c.383G>A NP_001393546.1:p.Arg128Lys missense NM_001406618.1:c.383G>A NP_001393547.1:p.Arg128Lys missense NM_001406619.1:c.383G>A NP_001393548.1:p.Arg128Lys missense NM_001406620.1:c.383G>A NP_001393549.1:p.Arg128Lys missense NM_001406621.1:c.383G>A NP_001393550.1:p.Arg128Lys missense NM_001406622.1:c.383G>A NP_001393551.1:p.Arg128Lys missense NM_001406623.1:c.383G>A NP_001393552.1:p.Arg128Lys missense NM_001406624.1:c.383G>A NP_001393553.1:p.Arg128Lys missense NM_001406625.1:c.383G>A NP_001393554.1:p.Arg128Lys missense NM_001406626.1:c.-206G>A 5 prime UTR NM_001406627.1:c.-206G>A 5 prime UTR NM_001406628.1:c.-206G>A 5 prime UTR NM_001406629.1:c.-348G>A 5 prime UTR NM_001406630.1:c.-348G>A 5 prime UTR NR_176214.1:n.963G>A non-coding transcript variant NR_176215.1:n.963G>A non-coding transcript variant NR_176216.1:n.830G>A non-coding transcript variant NR_176217.1:n.963G>A non-coding transcript variant NR_176218.1:n.963G>A non-coding transcript variant NC_000009.12:g.132912449C>T NC_000009.11:g.135787836C>T NG_012386.1:g.37185G>A LRG_486:g.37185G>A LRG_486t1:c.746G>A LRG_486p1:p.Arg249Lys - Protein change
- R128K, R198K, R249K
- Other names
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- Canonical SPDI
- NC_000009.12:132912448:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| TSC1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4843 | 4901 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV003505860.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Dec 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 1
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004365960.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 249 of the TSC1 protein (p.Arg249Lys). … (more)
This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 249 of the TSC1 protein (p.Arg249Lys). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 95%. 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. (less)
|
Comment:
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 249 of the TSC1 protein (p.Arg249Lys). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function with a negative predictive value of 95%. 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.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated Sep 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.