In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); A different missense change at this residue (V1646G) has been reported in the published literature (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011); This variant is associated with the following publications: (PMID: 18466115, 34992632, 32461669, 21309039, 18854862)
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.4936G>A (p.Val1646Met)
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.
(4)
Help
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.
Pathogenic/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000548.5(TSC2):c.4936G>A (p.Val1646Met)
Variation ID: 424444 Accession: VCV000424444.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2086818 (GRCh38) [ NCBI UCSC ] 16: 2136819 (GRCh37) [ 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 Apr 27, 2017 Feb 28, 2024 Mar 22, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.4936G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Val1646Met missense NM_001077183.3:c.4735G>A NP_001070651.1:p.Val1579Met missense NM_001114382.3:c.4867G>A NP_001107854.1:p.Val1623Met missense NM_001318827.2:c.4627G>A NP_001305756.1:p.Val1543Met missense NM_001318829.2:c.4591G>A NP_001305758.1:p.Val1531Met missense NM_001318831.2:c.4204G>A NP_001305760.1:p.Val1402Met missense NM_001318832.2:c.4768G>A NP_001305761.1:p.Val1590Met missense NM_001363528.2:c.4738G>A NP_001350457.1:p.Val1580Met missense NM_001370404.1:c.4804G>A NP_001357333.1:p.Val1602Met missense NM_001370405.1:c.4807G>A NP_001357334.1:p.Val1603Met missense NM_021055.3:c.4807G>A NP_066399.2:p.Val1603Met missense NC_000016.10:g.2086818G>A NC_000016.9:g.2136819G>A NG_005895.1:g.42513G>A NG_008617.1:g.56403C>T LRG_487:g.42513G>A LRG_487t1:c.4936G>A - Protein change
- V1646M, V1602M, V1531M, V1623M, V1579M, V1580M, V1603M, V1402M, V1543M, V1590M
- Other names
- -
- Canonical SPDI
- NC_000016.10:2086817:G:A
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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. |
|||
| TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10758 | 10957 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 22, 2023 | RCV000480140.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2022 | RCV000555170.12 |
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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Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002041009.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
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Likely pathogenic
(Mar 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000574252.5
First in ClinVar: Apr 27, 2017 Last updated: Apr 09, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); A different missense change at this residue (V1646G) has been reported in the published literature (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011); This variant is associated with the following publications: (PMID: 18466115, 34992632, 32461669, 21309039, 18854862) (less)
|
|
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Pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000644581.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 424444). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 21520333; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1646 of the TSC2 protein (p.Val1646Met). (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013526.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000424444 / PMID: 32461669) and different missense changes at the same codon (p.Val1646Gly, p.Val1646Leu / ClinVar ID: VCV001472268, VCV001490108 / PMID: 18854862) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 32461669, 34992632). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 34992632). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Autism (present) , Renal cyst (present) , Seizure (present) , Intellectual disability, mild (present)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 424444). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 21520333; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1646 of the TSC2 protein (p.Val1646Met).
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000424444 / PMID: 32461669) and different missense changes at the same codon (p.Val1646Gly, p.Val1646Leu / ClinVar ID: VCV001472268, VCV001490108 / PMID: 18854862) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 32461669, 34992632). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 34992632). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); A different missense change at this residue (V1646G) has been reported in the published literature (Coevoets et al., 2009; Hoogeveen-Westerveld et al., 2011); This variant is associated with the following publications: (PMID: 18466115, 34992632, 32461669, 21309039, 18854862)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 424444). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 21520333; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1646 of the TSC2 protein (p.Val1646Met).
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000424444 / PMID: 32461669) and different missense changes at the same codon (p.Val1646Gly, p.Val1646Leu / ClinVar ID: VCV001472268, VCV001490108 / PMID: 18854862) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 32461669, 34992632). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 34992632). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort. | Yao R | Frontiers in genetics | 2021 | PMID: 34992632 |
| TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study. | Ogórek B | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32461669 |
| LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
| A reliable cell-based assay for testing unclassified TSC2 gene variants. | Coevoets R | European journal of human genetics : EJHG | 2009 | PMID: 18854862 |
Text-mined citations for rs1064796970 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.