NM_006180.6(NTRK2):c.1301A>G (p.Tyr434Cys) AND Developmental and epileptic encephalopathy, 58

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 21, 2018
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:: RCV000577864.7

Allele description [Variation Report for NM_006180.6(NTRK2):c.1301A>G (p.Tyr434Cys)]

NM_006180.6(NTRK2):c.1301A>G (p.Tyr434Cys)

Gene:

NTRK2:neurotrophic receptor tyrosine kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q21.33

Genomic location:

Preferred name:

NM_006180.6(NTRK2):c.1301A>G (p.Tyr434Cys)

HGVS:

NC_000009.12:g.84751990A>G
NG_012201.2:g.88440A>G
NM_001007097.3:c.1301A>G
NM_001018064.3:c.1301A>G
NM_001018065.2:c.1301A>G
NM_001018066.3:c.1301A>G
NM_001291937.2:c.1262A>G
NM_001369532.1:c.1301A>G
NM_001369533.1:c.1301A>G
NM_001369534.1:c.1265A>G
NM_001369535.1:c.833A>G
NM_001369536.1:c.833A>G
NM_001369537.1:c.1301A>G
NM_001369538.1:c.1301A>G
NM_001369539.1:c.1301A>G
NM_001369540.1:c.1301A>G
NM_001369541.1:c.1301A>G
NM_001369542.1:c.1301A>G
NM_001369543.1:c.1301A>G
NM_001369544.1:c.1301A>G
NM_001369545.1:c.1301A>G
NM_001369546.1:c.1262A>G
NM_001369547.1:c.1301A>G
NM_001369548.1:c.1301A>G
NM_001369549.1:c.1301A>G
NM_001369550.1:c.833A>G
NM_001369551.1:c.833A>G
NM_001369552.1:c.833A>G
NM_006180.6:c.1301A>GMANE SELECT
NP_001007098.1:p.Tyr434Cys
NP_001018074.1:p.Tyr434Cys
NP_001018075.1:p.Tyr434Cys
NP_001018076.1:p.Tyr434Cys
NP_001278866.1:p.Tyr421Cys
NP_001356461.1:p.Tyr434Cys
NP_001356462.1:p.Tyr434Cys
NP_001356463.1:p.Tyr422Cys
NP_001356464.1:p.Tyr278Cys
NP_001356465.1:p.Tyr278Cys
NP_001356466.1:p.Tyr434Cys
NP_001356467.1:p.Tyr434Cys
NP_001356468.1:p.Tyr434Cys
NP_001356469.1:p.Tyr434Cys
NP_001356470.1:p.Tyr434Cys
NP_001356471.1:p.Tyr434Cys
NP_001356472.1:p.Tyr434Cys
NP_001356473.1:p.Tyr434Cys
NP_001356474.1:p.Tyr434Cys
NP_001356475.1:p.Tyr421Cys
NP_001356476.1:p.Tyr434Cys
NP_001356477.1:p.Tyr434Cys
NP_001356478.1:p.Tyr434Cys
NP_001356479.1:p.Tyr278Cys
NP_001356480.1:p.Tyr278Cys
NP_001356481.1:p.Tyr278Cys
NP_006171.2:p.Tyr434Cys
NP_006171.2:p.Tyr434Cys
NC_000009.11:g.87366905A>G
NM_006180.3:c.1301A>G
NM_006180.4:c.1301A>G
p.Tyr434Cys

Protein change:

Y278C; TYR434CYS

Links:

OMIM: 600456.0003; dbSNP: rs886041091

NCBI 1000 Genomes Browser:

rs886041091

Molecular consequence:

NM_001007097.3:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018064.3:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018065.2:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018066.3:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001291937.2:c.1262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369532.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369533.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369534.1:c.1265A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369535.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369536.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369537.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369538.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369539.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369540.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369541.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369542.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369543.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369544.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369545.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369546.1:c.1262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369547.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369548.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369549.1:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369550.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369551.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369552.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006180.6:c.1301A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 58
Synonyms:: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 58
Identifiers:: MONDO: MONDO:0033367; MedGen: C4693367; OMIM: 617830

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000328689	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (HA_assertions_20161101)	Pathogenic (Nov 2, 2017)	de novo	research	Citation Link,
SCV000679672	OMIM	no assertion criteria provided	Pathogenic (Nov 9, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001142594	Undiagnosed Diseases Network, NIH	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 21, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000328689

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha

criteria provided, single submitter

(HA_assertions_20161101)

Pathogenic
(Nov 2, 2017)

de novo

research

Citation Link,

SCV000679672

OMIM

no assertion criteria provided

Pathogenic
(Nov 9, 2020)

germline

literature only

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

SCV001142594

Undiagnosed Diseases Network, NIH

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 21, 2018)

de novo

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
White	de novo	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.

Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, et al.

Am J Hum Genet. 2017 Nov 2;101(5):664-685. doi: 10.1016/j.ajhg.2017.09.008.

PubMed [citation]

PMID:: 29100083
PMCID:: PMC5673604

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

Details of each submission

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000328689.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

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

From OMIM, SCV000679672.2

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

Description

In 4 unrelated patients with developmental and epileptic encephalopathy-58 (DEE58; 617830), Hamdan et al. (2017) identified a de novo heterozygous c.1301A-G transition (c.1301A-G, NM_006180.4) in the NTRK2 gene, resulting in a tyr434-to-cys (Y434C) substitution at the beginning of the transmembrane domain. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a gain-of-function or dominant-negative effect. The patients had onset of seizures in the first days to months of life.

#	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 Undiagnosed Diseases Network, NIH, SCV001142594.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	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	de novo	yes	not provided	blood	not provided		1	not provided	1	not provided

Last Updated: Oct 20, 2024

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