NM_002529.4(NTRK1):c.2281C>T (p.Arg761Trp) AND Hereditary insensitivity to pain with anhidrosis

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000674105.12

Allele description [Variation Report for NM_002529.4(NTRK1):c.2281C>T (p.Arg761Trp)]

NM_002529.4(NTRK1):c.2281C>T (p.Arg761Trp)

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.2281C>T (p.Arg761Trp)

HGVS:

NC_000001.11:g.156881532C>T
NG_007493.1:g.70783C>T
NM_001007792.1:c.2173C>T
NM_001012331.2:c.2263C>T
NM_002529.4:c.2281C>TMANE SELECT
NP_001007793.1:p.Arg725Trp
NP_001012331.1:p.Arg755Trp
NP_001012331.1:p.Arg755Trp
NP_002520.2:p.Arg761Trp
NP_002520.2:p.Arg761Trp
LRG_261t1:c.2173C>T
LRG_261t2:c.2263C>T
LRG_261t3:c.2281C>T
LRG_261:g.70783C>T
LRG_261p1:p.Arg725Trp
LRG_261p2:p.Arg755Trp
LRG_261p3:p.Arg761Trp
NC_000001.10:g.156851324C>T
NM_001012331.1:c.2263C>T
NM_002529.3:c.2281C>T

Protein change:

R725W

Links:

dbSNP: rs759637817

NCBI 1000 Genomes Browser:

rs759637817

Molecular consequence:

NM_001007792.1:c.2173C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001012331.2:c.2263C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002529.4:c.2281C>T - 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

Recent activity

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histone-binding protein RBBP7 [Mus musculus]
histone-binding protein RBBP7 [Mus musculus]
gi|157909799|ref|NP_033057.3|

Protein
PREDICTED: Homo sapiens mitogen-activated protein kinase 14 (MAPK14), transcript...
PREDICTED: Homo sapiens mitogen-activated protein kinase 14 (MAPK14), transcript variant X11, misc_RNA
gi|2217359759|ref|XR_926065.3|

Nucleotide
Homo sapiens mRNA; cDNA DKFZp434J1672 (from clone DKFZp434J1672); partial cds
Homo sapiens mRNA; cDNA DKFZp434J1672 (from clone DKFZp434J1672); partial cds
gi|6599159|emb|AL133578.1|

Nucleotide
fadJ [Acinetobacter pittii PHEA-2]
fadJ [Acinetobacter pittii PHEA-2]
Gene ID:11636846

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000799381	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 17, 2018)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16373086, 28192073, 11668614 Citation Link,
SCV000821402	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11668614, 16373086, 19651702, 28192073, 28492532
SCV002020172	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 25, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002600302	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11668614, 28192073, 19651702, 16373086 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000799381.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000821402.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 755 of the NTRK1 protein (p.Arg755Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with congenital insensitivity to pain with anhidrosis/ hereditary sensory and autonomic neuropathy (PMID: 11668614, 16373086, 19651702, 28192073). This variant is also known as p.Arg761Trp. ClinVar contains an entry for this variant (Variation ID: 557905). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NTRK1 protein function. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020172.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600302.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: NTRK1 c.2263C>T (p.Arg755Trp) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 227242 control chromosomes. c.2263C>T has been reported in the literature as biallelic compound heterozygous or homozygous genotypes in multiple individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (example, Indo_2001, Veerpoorten_2006, Rotthier_2009, Lv_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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