NM_002529.4(NTRK1):c.207_208del (p.Glu70fs) AND Hereditary insensitivity to pain with anhidrosis

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000022807.22

Allele description [Variation Report for NM_002529.4(NTRK1):c.207_208del (p.Glu70fs)]

NM_002529.4(NTRK1):c.207_208del (p.Glu70fs)

Gene:

NTRK1:neurotrophic receptor tyrosine kinase 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1q23.1

Genomic location:

Preferred name:

NM_002529.4(NTRK1):c.207_208del (p.Glu70fs)

HGVS:

NC_000001.11:g.156861141_156861142del
NG_007493.1:g.50392_50393del
NM_001007792.1:c.123-3213_123-3212del
NM_001012331.2:c.207_208del
NM_002529.4:c.207_208delMANE SELECT
NP_001012331.1:p.Glu70fs
NP_002520.2:p.Glu70fs
NP_002520.2:p.Glu70fs
LRG_261t1:c.123-3213_123-3212del
LRG_261t3:c.207_208del
LRG_261:g.50392_50393del
LRG_261p3:p.Glu70fs
NC_000001.10:g.156830933_156830934del
NM_002529.3:c.207_208del

Protein change:

E70fs

Links:

OMIM: 191315.0014; dbSNP: rs398122810

NCBI 1000 Genomes Browser:

rs398122810

Molecular consequence:

NM_001012331.2:c.207_208del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002529.4:c.207_208del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001007792.1:c.123-3213_123-3212del - intron variant - [Sequence Ontology: SO:0001627]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000044096	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003523254	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19250380, 10982191, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000044096

OMIM

no assertion criteria provided

Pathogenic
(Mar 1, 2009)

germline

literature only

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

SCV003523254

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 27, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Skoura - a genetic island for congenital insensitivity to pain and anhidrosis among Moroccan Jews, as determined by a novel mutation in the NTRK1 gene.

Suriu C, Khayat M, Weiler M, Kfir N, Cohen C, Zinger A, Aslanidis C, Schmitz G, Falik-Zaccai TC.

Clin Genet. 2009 Mar;75(3):230-6. doi: 10.1111/j.1399-0004.2008.01143.x.

PubMed [citation]

PMID:: 19250380

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, Mardy S, Awaya Y, Nihei K, Endo F, Matsuda I, Indo Y.

Hum Genet. 2000 Jan;106(1):116-24. Erratum in: Hum Genet 2000 May;106(5):575.

PubMed [citation]

PMID:: 10982191

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000044096.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 sibs with congenital insensitivity to pain with anhidrosis (CIPA; 256800), whose unrelated Israeli parents were of Moroccan Jewish descent, Suriu et al. (2009) identified a homozygous 2-bp deletion (207delTG) in exon 1 of the NTRK1 gene, resulting in a frameshift and premature termination at codon 86. Each unaffected parent was heterozygous for the mutation. This mutation was identified in the heterozygous state in a carrier from a second unrelated family of Moroccan Jewish origin in which 2 individuals had CIPA and died. The mutation was not found in 600 control chromosomes. Haplotype analysis indicated shared markers surrounding the mutant allele. Both families originated from Skoura, a small oasis village along the Valley of a Thousand Kasbahs in southern Morocco. Most members of the Jewish families residing there had immigrated to Israel in the 1950s. The common ancestry suggested that 207delTG may be a founder mutation.

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

From Invitae, SCV003523254.2

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

Description

ClinVar contains an entry for this variant (Variation ID: 29920). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.207-208 delTG. This premature translational stop signal has been observed in individual(s) with congenital insensitivity to pain and anhidrosis (PMID: 19250380). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs398122810, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Glu70Alafs*16) in the NTRK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NTRK1 are known to be pathogenic (PMID: 10982191).

#	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: Feb 20, 2024

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