NM_000162.5(GCK):c.1361C>A (p.Ala454Glu) AND Microcephaly, normal intelligence and immunodeficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 27, 2024
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:: RCV004539920.1

Allele description [Variation Report for NM_000162.5(GCK):c.1361C>A (p.Ala454Glu)]

NM_000162.5(GCK):c.1361C>A (p.Ala454Glu)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1361C>A (p.Ala454Glu)

Other names:

NM_000162.5(GCK):c.1361C>A; p.Ala454Glu

HGVS:

NC_000007.14:g.44145173G>T
NG_008847.2:g.57998C>A
NM_000162.5:c.1361C>AMANE SELECT
NM_001354800.1:c.1361C>A
NM_001354801.1:c.350C>A
NM_001354802.1:c.221C>A
NM_001354803.2:c.395C>A
NM_033507.3:c.1364C>A
NM_033508.3:c.1358C>A
NP_000153.1:p.Ala454Glu
NP_001341729.1:p.Ala454Glu
NP_001341730.1:p.Ala117Glu
NP_001341731.1:p.Ala74Glu
NP_001341732.1:p.Ala132Glu
NP_277042.1:p.Ala455Glu
NP_277043.1:p.Ala453Glu
LRG_1074t1:c.1361C>A
LRG_1074t2:c.1364C>A
LRG_1074:g.57998C>A
LRG_1074p1:p.Ala454Glu
LRG_1074p2:p.Ala455Glu
NC_000007.13:g.44184772G>T
NM_000162.3:c.1361C>A

Protein change:

A117E

Links:

dbSNP: rs1057524900

NCBI 1000 Genomes Browser:

rs1057524900

Molecular consequence:

NM_000162.5:c.1361C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1361C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.350C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354802.1:c.221C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.395C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1364C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1358C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Microcephaly, normal intelligence and immunodeficiency (NBS)
Synonyms:: IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY; SEEMANOVA SYNDROME II; Nijmegen breakage syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009623; MedGen: C0398791; Orphanet: 647; OMIM: 251260

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005040818	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 27, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16602010, 17204055, 20337973, 19790256, 24097065, 36257325 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005040818

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 27, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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

Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents.

Feigerlová E, Pruhová S, Dittertová L, Lebl J, Pinterová D, Kolostová K, Cerná M, Pedersen O, Hansen T.

Eur J Pediatr. 2006 Jul;165(7):446-52. Epub 2006 Apr 7.

PubMed [citation]

PMID:: 16602010

Six novel mutations in the GCK gene in MODY patients.

Pinterova D, Ek J, Kolostova K, Pruhova S, Novota P, Romzova M, Feigerlova E, Cerna M, Lebl J, Pedersen O, Hansen T.

Clin Genet. 2007 Jan;71(1):95-6. No abstract available.

PubMed [citation]

PMID:: 17204055

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005040818.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: NBN c.1361C>A (p.Ser454Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251230 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1361C>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Jul 7, 2024

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