This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID: 18955016, 10861667, 28328124, ClinVar ID: 21306]
ClinVar Genomic variation as it relates to human health
NM_002529.4(NTRK1):c.1860_1861insT (p.Pro621fs)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002529.4(NTRK1):c.1860_1861insT (p.Pro621fs)
Variation ID: 21306 Accession: VCV000021306.14
- Type and length
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Insertion, 1 bp
- Location
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Cytogenetic: 1q23.1 1: 156879176-156879177 (GRCh38) [ NCBI UCSC ] 1: 156848968-156848969 (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 Oct 28, 2023 May 3, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002529.4:c.1860_1861insT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002520.2:p.Pro621fs frameshift NM_001007792.1:c.1752_1753insT NP_001007793.1:p.Pro585fs frameshift NM_001012331.2:c.1842_1843insT NP_001012331.1:p.Pro615fs frameshift NC_000001.11:g.156879176_156879177insT NC_000001.10:g.156848968_156848969insT NG_007493.1:g.68427_68428insT LRG_261:g.68427_68428insT LRG_261t1:c.1752_1753insT LRG_261p1:p.Pro585fs LRG_261t2:c.1842_1843insT LRG_261p2:p.Pro615fs LRG_261t3:c.1860_1861insT LRG_261p3:p.Pro621fs - Protein change
- P585fs, P621fs, P615fs
- Other names
- -
- Canonical SPDI
- NC_000001.11:156879176::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. |
|||
| NTRK1 | - | - |
GRCh38 GRCh37 |
1341 | 1526 | |
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 (7) |
criteria provided, multiple submitters, no conflicts
|
May 3, 2023 | RCV000020469.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 3, 2022 | RCV000479042.5 |
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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|---|---|---|---|---|---|
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Pathogenic
(Sep 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary insensitivity to pain with anhidrosis
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520941.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID: … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID: 18955016, 10861667, 28328124, ClinVar ID: 21306] (less)
|
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Pathogenic
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary insensitivity to pain with anhidrosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002237779.1
First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary insensitivity to pain with anhidrosis
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573044.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021306 / PMID: 10861667). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Recurrent fever (present) , Recurrent fractures (present) , Seizure (present)
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Pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000565335.5
First in ClinVar: Apr 27, 2017 Last updated: May 06, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34405299, 28328124, 18955016, 10861667, 31841741, 32056211, 20301726, 34732685) (less)
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Pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary insensitivity to pain with anhidrosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027677.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Criteria applied: PVS1,PM3_STR,PM2_SUP
Clinical Features:
Oligodontia (present) , Anhidrosis (present) , Pain insensitivity (present) , Sensory neuropathy (present) , Scoliosis (present) , Nail dysplasia (present) , Chronic cutaneous wound (present) … (more)
Oligodontia (present) , Anhidrosis (present) , Pain insensitivity (present) , Sensory neuropathy (present) , Scoliosis (present) , Nail dysplasia (present) , Chronic cutaneous wound (present) , Short stature (present) (less)
Sex: female
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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: SCV004048753.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Jun 19, 2000)
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no assertion criteria provided
Method: literature only
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INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033349.4
First in ClinVar: Apr 04, 2013 Last updated: May 17, 2019 |
Comment on evidence:
In patients with congenital insensitivity to pain (CIPA; 256800) from 16 Bedouin families from the southern Israeli-Negev, Shatzky et al. (2000) identified a 1-bp insertion … (more)
In patients with congenital insensitivity to pain (CIPA; 256800) from 16 Bedouin families from the southern Israeli-Negev, Shatzky et al. (2000) identified a 1-bp insertion (1926insT) in the NTRK1 gene. The mutation was used for prenatal diagnosis in 6 cases. (less)
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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: SCV000040902.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Founder variant in Israeli Bedouins
|
Comment:
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021306 / PMID: 10861667). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34405299, 28328124, 18955016, 10861667, 31841741, 32056211, 20301726, 34732685)
Comment:
Criteria applied: PVS1,PM3_STR,PM2_SUP
Comment:
Founder variant in Israeli Bedouins
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 variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID: 18955016, 10861667, 28328124, ClinVar ID: 21306]
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021306 / PMID: 10861667). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34405299, 28328124, 18955016, 10861667, 31841741, 32056211, 20301726, 34732685)
Comment:
Criteria applied: PVS1,PM3_STR,PM2_SUP
Comment:
Founder variant in Israeli Bedouins
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| NTRK1 Congenital Insensitivity to Pain with Anhidrosis. | Adam MP | - | 2020 | PMID: 20301726 |
| Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype. | Altassan R | American journal of medical genetics. Part A | 2017 | PMID: 28328124 |
| Abnormal neutrophil chemotactic activity in children with congenital insensitivity to pain with anhidrosis (CIPA): the role of nerve growth factor. | Beigelman A | Clinical immunology (Orlando, Fla.) | 2009 | PMID: 18955016 |
| 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 |
| Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. | Shatzky S | American journal of medical genetics | 2000 | PMID: 10861667 |
Text-mined citations for rs80356676 ...
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.