ClinVar Genomic variation as it relates to human health
NM_002529.4(NTRK1):c.2020G>T (p.Asp674Tyr)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002529.4(NTRK1):c.2020G>T (p.Asp674Tyr)
Variation ID: 21307 Accession: VCV000021307.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q23.1 1: 156879336 (GRCh38) [ NCBI UCSC ] 1: 156849128 (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 4, 2013 Feb 14, 2024 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002529.4:c.2020G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002520.2:p.Asp674Tyr missense NM_001007792.1:c.1912G>T NP_001007793.1:p.Asp638Tyr missense NM_001012331.2:c.2002G>T NP_001012331.1:p.Asp668Tyr missense NC_000001.11:g.156879336G>T NC_000001.10:g.156849128G>T NG_007493.1:g.68587G>T LRG_261:g.68587G>T LRG_261t1:c.1912G>T LRG_261p1:p.Asp638Tyr LRG_261t3:c.2020G>T LRG_261p3:p.Asp674Tyr P04629:p.Asp674Tyr - Protein change
- D638Y, D668Y, D674Y
- Other names
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- Canonical SPDI
- NC_000001.11:156879335:G: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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 | ||
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HI score
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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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NTRK1 | - | - |
GRCh38 GRCh37 |
1328 | 1505 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000020470.9 |
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
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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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Likely pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary insensitivity to pain with anhidrosis
Affected status: yes
Allele origin:
maternal
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3billion
Accession: SCV002012169.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000041, PM2). The variant was observed in trans with … (more)
It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000041, PM2). The variant was observed in trans with a pathogenic variant (NM_002529.3:c.851-33T>A) as compound heterozygous (3billion dataset, PM3).In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.970, PP3). Patient's phenotype is considered compatible with Insensitivity to pain, congenital, with anhidrosis (3billion dataset, PP4).The variant has been reported as pathogenic/likely pathogenic without evidence for the classification (ClinVar ID:VCV000021307.2). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Recurrent fever (present) , Anhidrosis (present) , Self-mutilation (present) , Generalized hypotonia (present) , Pain insensitivity (present) , Delayed gross motor development (present)
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary insensitivity to pain with anhidrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004048763.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Apr 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary insensitivity to pain with anhidrosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003523911.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with NTRK1-related conditions (PMID: 10982191, 28177573, 32807182, 32901917). In at least one individual the data is consistent … (more)
This missense change has been observed in individual(s) with NTRK1-related conditions (PMID: 10982191, 28177573, 32807182, 32901917). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Asp674Tyr. ClinVar contains an entry for this variant (Variation ID: 21307). 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 NTRK1 protein function. Experimental studies have shown that this missense change affects NTRK1 function (PMID: 11719521). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs80356677, gnomAD 0.006%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 668 of the NTRK1 protein (p.Asp668Tyr). (less)
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Pathogenic
(Nov 16, 2021)
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no assertion criteria provided
Method: research
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Hereditary insensitivity to pain with anhidrosis
Affected status: yes
Allele origin:
germline
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Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Accession: SCV002549899.1
First in ClinVar: Jul 26, 2022 Last updated: Jul 26, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary insensitivity to pain with anhidrosis
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040903.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Pathogenic variants common in Japanese population
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE. | Seo GH | Clinical genetics | 2020 | PMID: 32901917 |
Clinical, genomics and networking analyses of a high-altitude native American Ecuadorian patient with congenital insensitivity to pain with anhidrosis: a case report. | López-Cortés A | BMC medical genomics | 2020 | PMID: 32807182 |
NTRK1 Congenital Insensitivity to Pain with Anhidrosis. | Adam MP | - | 2020 | PMID: 20301726 |
Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies. | Nam TS | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 28177573 |
Novel pathogenic mechanisms of congenital insensitivity to pain with anhidrosis genetic disorder unveiled by functional analysis of neurotrophic tyrosine receptor kinase type 1/nerve growth factor receptor mutations. | Miranda C | The Journal of biological chemistry | 2002 | PMID: 11719521 |
Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. | Indo Y | Human mutation | 2001 | PMID: 11748840 |
Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency. | Indo Y | Human mutation | 2001 | PMID: 11668614 |
Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families. | Miura Y | Human genetics | 2000 | PMID: 10982191 |
Text-mined citations for rs80356677 ...
HelpRecord last updated Feb 14, 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.