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

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 22, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000516618.15

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:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000613470	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Uncertain significance (Dec 14, 2020)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31063852, 26467025
SCV001875150	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 22, 2024)	germline	clinical testing	Citation Link,
SCV002107962	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31063852, 36257325, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000613470

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics criteria)

Uncertain significance
(Dec 14, 2020)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001875150

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Oct 22, 2024)

germline

clinical testing

Citation Link,

SCV002107962

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 8, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

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

See all PubMed Citations (4)

Details of each submission

From Athena Diagnostics, SCV000613470.3

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

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

From GeneDx, SCV001875150.6

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing; in the absence of RNA/functional studies the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 36257325, 31063852)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002107962.3

#	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 447426). This missense change has been observed in individuals with autosomal dominant maturity onset diabetes of the young and/or maturity-onset diabetes of the young (PMID: 31063852, 36257325; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 317 of the GCK protein (p.His317Gln).

#	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

ClinVar

Relating variation to medicine