This missense change has been observed in individual(s) with NTRK2-related conditions (PMID: 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 268204). 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 NTRK2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 434 of the NTRK2 protein (p.Tyr434Cys).
ClinVar Genomic variation as it relates to human health
NM_006180.6(NTRK2):c.1301A>G (p.Tyr434Cys)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006180.6(NTRK2):c.1301A>G (p.Tyr434Cys)
Variation ID: 268204 Accession: VCV000268204.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q21.33 9: 84751990 (GRCh38) [ NCBI UCSC ] 9: 87366905 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 26, 2018 Oct 20, 2024 Aug 17, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006180.6:c.1301A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006171.2:p.Tyr434Cys missense NM_001007097.3:c.1301A>G NP_001007098.1:p.Tyr434Cys missense NM_001018064.3:c.1301A>G NP_001018074.1:p.Tyr434Cys missense NM_001018065.2:c.1301A>G NP_001018075.1:p.Tyr434Cys missense NM_001018066.3:c.1301A>G NP_001018076.1:p.Tyr434Cys missense NM_001291937.2:c.1262A>G NP_001278866.1:p.Tyr421Cys missense NM_001369532.1:c.1301A>G NP_001356461.1:p.Tyr434Cys missense NM_001369533.1:c.1301A>G NP_001356462.1:p.Tyr434Cys missense NM_001369534.1:c.1265A>G NP_001356463.1:p.Tyr422Cys missense NM_001369535.1:c.833A>G NP_001356464.1:p.Tyr278Cys missense NM_001369536.1:c.833A>G NP_001356465.1:p.Tyr278Cys missense NM_001369537.1:c.1301A>G NP_001356466.1:p.Tyr434Cys missense NM_001369538.1:c.1301A>G NP_001356467.1:p.Tyr434Cys missense NM_001369539.1:c.1301A>G NP_001356468.1:p.Tyr434Cys missense NM_001369540.1:c.1301A>G NP_001356469.1:p.Tyr434Cys missense NM_001369541.1:c.1301A>G NP_001356470.1:p.Tyr434Cys missense NM_001369542.1:c.1301A>G NP_001356471.1:p.Tyr434Cys missense NM_001369543.1:c.1301A>G NP_001356472.1:p.Tyr434Cys missense NM_001369544.1:c.1301A>G NP_001356473.1:p.Tyr434Cys missense NM_001369545.1:c.1301A>G NP_001356474.1:p.Tyr434Cys missense NM_001369546.1:c.1262A>G NP_001356475.1:p.Tyr421Cys missense NM_001369547.1:c.1301A>G NP_001356476.1:p.Tyr434Cys missense NM_001369548.1:c.1301A>G NP_001356477.1:p.Tyr434Cys missense NM_001369549.1:c.1301A>G NP_001356478.1:p.Tyr434Cys missense NM_001369550.1:c.833A>G NP_001356479.1:p.Tyr278Cys missense NM_001369551.1:c.833A>G NP_001356480.1:p.Tyr278Cys missense NM_001369552.1:c.833A>G NP_001356481.1:p.Tyr278Cys missense NC_000009.12:g.84751990A>G NC_000009.11:g.87366905A>G NG_012201.2:g.88440A>G - Protein change
- Y434C, Y422C, Y278C, Y421C
- Other names
- -
- Canonical SPDI
- NC_000009.12:84751989:A:G
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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.
- -
- 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. |
|||
| NTRK2 | - | - |
GRCh38 GRCh37 |
662 | 714 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 21, 2018 | RCV000577864.7 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 17, 2023 | RCV000782078.32 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 2, 2017 | RCV001265761.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002234206.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with NTRK2-related conditions (PMID: 29100083). In at least one individual the variant was observed to be de … (more)
This missense change has been observed in individual(s) with NTRK2-related conditions (PMID: 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 268204). 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 NTRK2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 434 of the NTRK2 protein (p.Tyr434Cys). (less)
|
|
|
Pathogenic
(Aug 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500544.23
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 02, 2017)
|
criteria provided, single submitter
Method: research
|
Developmental and epileptic encephalopathy, 58
Affected status: yes
Allele origin:
de novo
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000328689.3 First in ClinVar: Nov 19, 2016 Last updated: Feb 13, 2018 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000920549.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
|
|
|
Likely pathogenic
(Aug 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 58
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Undiagnosed Diseases Network, NIH
Accession: SCV001142594.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Spasticity (present) , Seizures (present) , Rotary nystagmus (present) , Reduced brain N-acetyl aspartate level by MRS (present) , Progressive visual loss (present) , Optic … (more)
Spasticity (present) , Seizures (present) , Rotary nystagmus (present) , Reduced brain N-acetyl aspartate level by MRS (present) , Progressive visual loss (present) , Optic atrophy (present) , Myopia (present) , Microcephaly (present) , Increased muscle fatiguability (present) , Headache (present) , Hamartoma (present) , Global developmental delay (present) , Episodic vomiting (present) , EEG with continuous slow activity (present) , Attenuation of retinal blood vessels (present) , Anti-multiple nuclear dots antibody positivity (present) , Ankle clonus (present) (less)
Age: 20-29 years
Sex: female
Ethnicity/Population group: White
Tissue: blood
|
|
|
Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762223.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Clinical Features:
Nystagmus (present) , Hypotonia (present) , Global developmental delay (present)
Sex: female
|
|
|
Likely pathogenic
(Nov 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001443930.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Oct 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001790578.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34889524, 29100083, 29652076, 31070779, 34426522, 33816068) (less)
|
|
|
Pathogenic
(Nov 09, 2020)
|
no assertion criteria provided
Method: literature only
|
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 58
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000679672.2
First in ClinVar: Jan 26, 2018 Last updated: Nov 14, 2020 |
Comment on evidence:
In 4 unrelated patients with developmental and epileptic encephalopathy-58 (DEE58; 617830), Hamdan et al. (2017) identified a de novo heterozygous c.1301A-G transition (c.1301A-G, NM_006180.4) in … (more)
In 4 unrelated patients with developmental and epileptic encephalopathy-58 (DEE58; 617830), Hamdan et al. (2017) identified a de novo heterozygous c.1301A-G transition (c.1301A-G, NM_006180.4) in the NTRK2 gene, resulting in a tyr434-to-cys (Y434C) substitution at the beginning of the transmembrane domain. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a gain-of-function or dominant-negative effect. The patients had onset of seizures in the first days to months of life. (less)
|
Comment:
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34889524, 29100083, 29652076, 31070779, 34426522, 33816068)
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 missense change has been observed in individual(s) with NTRK2-related conditions (PMID: 29100083). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 268204). 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 NTRK2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 434 of the NTRK2 protein (p.Tyr434Cys).
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34889524, 29100083, 29652076, 31070779, 34426522, 33816068)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. | Hamdan FF | American journal of human genetics | 2017 | PMID: 29100083 |
Text-mined citations for rs886041091 ...
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 Oct 20, 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.