NM_002529.4(NTRK1):c.1946G>A (p.Arg649Gln) AND Hereditary insensitivity to pain with anhidrosis

Clinical significance:Uncertain significance (Last evaluated: Oct 22, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001235402.2

Allele description [Variation Report for NM_002529.4(NTRK1):c.1946G>A (p.Arg649Gln)]

NM_002529.4(NTRK1):c.1946G>A (p.Arg649Gln)

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.1946G>A (p.Arg649Gln)
HGVS:
  • NC_000001.11:g.156879262G>A
  • NG_007493.1:g.68513G>A
  • NM_001007792.1:c.1838G>A
  • NM_001012331.1:c.1928G>A
  • NM_001012331.2:c.1928G>A
  • NM_002529.4:c.1946G>AMANE SELECT
  • NP_001007793.1:p.Arg613Gln
  • NP_001012331.1:p.Arg643Gln
  • NP_001012331.1:p.Arg643Gln
  • NP_002520.2:p.Arg649Gln
  • LRG_261t1:c.1838G>A
  • LRG_261t2:c.1928G>A
  • LRG_261:g.68513G>A
  • LRG_261p1:p.Arg613Gln
  • LRG_261p2:p.Arg643Gln
  • NC_000001.10:g.156849054G>A
  • NC_000001.10:g.156849054G>A
Protein change:
R613Q
Links:
dbSNP: rs786205449
NCBI 1000 Genomes Browser:
rs786205449
Molecular consequence:
  • NM_001007792.1:c.1838G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001012331.1:c.1928G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001012331.2:c.1928G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002529.4:c.1946G>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
SCV001408085Invitaecriteria provided, single submitter
Uncertain significance
(Oct 22, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype.

Altassan R, Saud HA, Masoodi TA, Dosssari HA, Khalifa O, Al-Zaidan H, Sakati N, Rhabeeni Z, Al-Hassnan Z, Binamer Y, Alhashemi N, Wade W, Al-Zayed Z, Al-Sayed M, Al-Muhaizea MA, Meyer B, Al-Owain M, Wakil SM.

Am J Med Genet A. 2017 Apr;173(4):1009-1016. doi: 10.1002/ajmg.a.38120.

PubMed [citation]
PMID:
28328124

Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.

Mardy S, Miura Y, Endo F, Matsuda I, Sztriha L, Frossard P, Moosa A, Ismail EA, Macaya A, Andria G, Toscano E, Gibson W, Graham GE, Indo Y.

Am J Hum Genet. 1999 Jun;64(6):1570-9.

PubMed [citation]
PMID:
10330344
PMCID:
PMC1377900
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001408085.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine with glutamine at codon 643 of the NTRK1 protein (p.Arg643Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the homozygous state in an individual affected with hereditary sensory and autonomic neuropathy (PMID: 28328124). ClinVar contains an entry for this variant (Variation ID: 190988). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C3). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg643 amino acid residue in NTRK1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330344, 29770739, 22653642, 11159935, 11719521). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant 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

Last Updated: Oct 25, 2021

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