NM_000162.5(GCK):c.951C>G (p.His317Gln) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 21, 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:: RCV003235263.3

Allele description [Variation Report for NM_000162.5(GCK):c.951C>G (p.His317Gln)]

NM_000162.5(GCK):c.951C>G (p.His317Gln)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.951C>G (p.His317Gln)

HGVS:

NC_000007.14:g.44146531G>C
NG_008847.2:g.56640C>G
NM_000162.5:c.951C>GMANE SELECT
NM_001354800.1:c.951C>G
NM_001354801.1:c.8+88C>G
NM_033507.3:c.954C>G
NM_033508.3:c.948C>G
NP_000153.1:p.His317Gln
NP_001341729.1:p.His317Gln
NP_277042.1:p.His318Gln
NP_277043.1:p.His316Gln
LRG_1074t1:c.951C>G
LRG_1074t2:c.954C>G
LRG_1074:g.56640C>G
LRG_1074p1:p.His317Gln
LRG_1074p2:p.His318Gln
NC_000007.13:g.44186130G>C
NM_000162.3:c.951C>G
p.HIS317GLN

Protein change:

H316Q

Links:

dbSNP: rs1379908545

NCBI 1000 Genomes Browser:

rs1379908545

Molecular consequence:

NM_001354801.1:c.8+88C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000162.5:c.951C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.951C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.954C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.948C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003934329	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 21, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 36257325, 31063852 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003934329

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 21, 2024)

germline

clinical testing

PubMed (2)
[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

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM; Geisinger-Regeneron DiscovEHR Collaboration., Frayling TF, Hattersley AT, Carey DJ, Weedon MN, Patel KA.

Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. doi: 10.1016/j.ajhg.2022.09.014. Epub 2022 Oct 17.

PubMed [citation]

PMID:: 36257325
PMCID:: PMC9674944

GCK-MODY in the US Monogenic Diabetes Registry: Description of 27 unpublished variants.

Sanyoura M, Letourneau L, Knight Johnson AE, Del Gaudio D, Greeley SAW, Philipson LH, Naylor RN.

Diabetes Res Clin Pract. 2019 May;151:231-236. doi: 10.1016/j.diabres.2019.04.017. Epub 2019 May 4.

PubMed [citation]

PMID:: 31063852
PMCID:: PMC6544496

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934329.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: GCK c.951C>G (p.His317Gln) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247832 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.951C>G has been reported in the literature in individuals suspected of Monogenic Diabetes (examples: Sanyoura_2019 and Mirshahi_2022). At-least one of these reports classified the variant as VUS (Sanyoura_2019). These reports do not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36257325, 31063852). ClinVar contains an entry for this variant (Variation ID: 447426). 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: Nov 3, 2024

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