NM_002529.4(NTRK1):c.2057G>A (p.Arg686His) AND Hereditary insensitivity to pain with anhidrosis

Clinical significance:Uncertain significance (Last evaluated: May 15, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000528062.5

Allele description [Variation Report for NM_002529.4(NTRK1):c.2057G>A (p.Arg686His)]

NM_002529.4(NTRK1):c.2057G>A (p.Arg686His)

Gene:
NTRK1:neurotrophic receptor tyrosine kinase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q23.1
Genomic location:
Preferred name:
NM_002529.4(NTRK1):c.2057G>A (p.Arg686His)
HGVS:
  • NC_000001.11:g.156880009G>A
  • NG_007493.1:g.69260G>A
  • NM_001007792.1:c.1949G>A
  • NM_001012331.1:c.2039G>A
  • NM_001012331.2:c.2039G>A
  • NM_002529.4:c.2057G>AMANE SELECT
  • NP_001007793.1:p.Arg650His
  • NP_001012331.1:p.Arg680His
  • NP_001012331.1:p.Arg680His
  • NP_002520.2:p.Arg686His
  • LRG_261t1:c.1949G>A
  • LRG_261t2:c.2039G>A
  • LRG_261:g.69260G>A
  • LRG_261p1:p.Arg650His
  • LRG_261p2:p.Arg680His
  • NC_000001.10:g.156849801G>A
Protein change:
R650H
Links:
dbSNP: rs754452975
NCBI 1000 Genomes Browser:
rs754452975
Molecular consequence:
  • NM_001007792.1:c.1949G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001012331.1:c.2039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001012331.2:c.2039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002529.4:c.2057G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary insensitivity to pain with anhidrosis (CIPA)
Synonyms:
FAMILIAL DYSAUTONOMIA, TYPE II; Insensitivity to pain, congenital, with anhidrosis; Neuropathy, congenital sensory, with anhidrosis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009746; MedGen: C0020074; Orphanet: 642; OMIM: 256800

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000626956Invitaecriteria provided, single submitter
Uncertain significance
(May 15, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000915361Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Apr 28, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001456801Natera, Inc.no assertion criteria providedUncertain significance
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Oral and craniofacial manifestations and two novel missense mutations of the NTRK1 gene identified in the patient with congenital insensitivity to pain with anhidrosis.

Gao L, Guo H, Ye N, Bai Y, Liu X, Yu P, Xue Y, Ma S, Wei K, Jin Y, Wen L, Xuan K.

PLoS One. 2013 Jun 14;8(6):e66863. doi: 10.1371/journal.pone.0066863. Print 2013.

PubMed [citation]
PMID:
23799134
PMCID:
PMC3682965

Details of each submission

From Invitae, SCV000626956.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine with histidine at codon 680 of the NTRK1 protein (p.Arg680His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs754452975, ExAC 0.006%). This variant has been reported in an individual affected with congenital insensitivity to pain with anhidrosis (PMID: 23799134). This variant is also referred to as p.Arg686His in the literature. ClinVar contains an entry for this variant (Variation ID: 194476). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on NTRK1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000915361.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The NTRK1 c.2039G>A (p.Arg680His) missense variant (also referred to as c.2057G>A, p.Arg686His), has been reported in one study in which it is found in a compound heterozygous state with a second missense variant in one individual with congenital insensitivity to pain with anhidrosis (Gao et al. 2013). The variant was also found in a heterozygous state in one of the unaffected parents. The p.Arg680His variant was absent from 100 controls and is reported at a frequency of 0.00006 in the South Asian population, however this is based on one allele so the variant is presumed to be rare. The evidence for this variant is limited. The p.Arg680His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for congenital insensitivity to pain with anhidrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001456801.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 25, 2021

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