NM_000162.5(GCK):c.452C>A (p.Ser151Tyr) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 15, 2021
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:: RCV002029930.4

Allele description [Variation Report for NM_000162.5(GCK):c.452C>A (p.Ser151Tyr)]

NM_000162.5(GCK):c.452C>A (p.Ser151Tyr)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.452C>A (p.Ser151Tyr)

HGVS:

NC_000007.14:g.44150987G>T
NG_008847.2:g.52184C>A
NM_000162.5:c.452C>AMANE SELECT
NM_001354800.1:c.452C>A
NM_033507.3:c.455C>A
NM_033508.3:c.449C>A
NP_000153.1:p.Ser151Tyr
NP_001341729.1:p.Ser151Tyr
NP_277042.1:p.Ser152Tyr
NP_277043.1:p.Ser150Tyr
LRG_1074t1:c.452C>A
LRG_1074t2:c.455C>A
LRG_1074:g.52184C>A
LRG_1074p1:p.Ser151Tyr
LRG_1074p2:p.Ser152Tyr
NC_000007.13:g.44190586G>T

Protein change:

S150Y

Links:

dbSNP: rs2128822050

NCBI 1000 Genomes Browser:

rs2128822050

Molecular consequence:

NM_000162.5:c.452C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.452C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.455C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.449C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002114223	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 15, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19564454, 24411943, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002114223

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 15, 2021)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families.

Lorini R, Klersy C, d'Annunzio G, Massa O, Minuto N, Iafusco D, Bellannè-Chantelot C, Frongia AP, Toni S, Meschi F, Cerutti F, Barbetti F; Italian Society of Pediatric Endocrinology and Diabetology (ISPED) Study Group..

Diabetes Care. 2009 Oct;32(10):1864-6. doi: 10.2337/dc08-2018. Epub 2009 Jun 29.

PubMed [citation]

PMID:: 19564454
PMCID:: PMC2752915

Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man.

Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, Edge JA, Stewart H, Alamiri E, Hussain K, Wallis S, de Vries L, Rubio-Cabezas O, Houghton JA, Edghill EL, Patch AM, Ellard S, Hattersley AT.

Cell Metab. 2014 Jan 7;19(1):146-54. doi: 10.1016/j.cmet.2013.11.021.

PubMed [citation]

PMID:: 24411943
PMCID:: PMC3887257

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002114223.3

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser151 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 19564454, 24411943), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tyrosine at codon 151 of the GCK protein (p.Ser151Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine.

#	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: Sep 29, 2024

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