NM_024408.4(NOTCH2):c.6004A>G (p.Asn2002Asp) AND Hajdu-Cheney syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 3, 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:: RCV002535322.4

Allele description [Variation Report for NM_024408.4(NOTCH2):c.6004A>G (p.Asn2002Asp)]

NM_024408.4(NOTCH2):c.6004A>G (p.Asn2002Asp)

Gene:

NOTCH2:notch receptor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p12

Genomic location:

Preferred name:

NM_024408.4(NOTCH2):c.6004A>G (p.Asn2002Asp)

HGVS:

NC_000001.11:g.119917688T>C
NG_008163.1:g.156966A>G
NM_024408.4:c.6004A>GMANE SELECT
NP_077719.2:p.Asn2002Asp
NC_000001.10:g.120460311T>C
NM_024408.3:c.6004A>G

Protein change:

N2002D

Links:

dbSNP: rs761367735

NCBI 1000 Genomes Browser:

rs761367735

Molecular consequence:

NM_024408.4:c.6004A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hajdu-Cheney syndrome (HJCYS)
Synonyms:: ACROOSTEOLYSIS WITH OSTEOPOROSIS AND CHANGES IN SKULL AND MANDIBLE; SERPENTINE FIBULA-POLYCYSTIC KIDNEY SYNDROME; Acroosteolysis dominant type
Identifiers:: MONDO: MONDO:0007057; MedGen: C0917715; Orphanet: 955; OMIM: 102500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003475750	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 3, 2023)	germline	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

SCV003475750

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 3, 2023)

germline

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	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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003475750.3

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

Description

ClinVar contains an entry for this variant (Variation ID: 597266). 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) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH2 protein function. 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. This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2002 of the NOTCH2 protein (p.Asn2002Asp). This variant is present in population databases (rs761367735, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NOTCH2-related conditions.

#	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 16, 2025

ClinVar

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